US20150197480A9 - Glucagon-like peptide 1 (glp-1) receptor modulators and uses thereof in regulating blood glucose levels - Google Patents
Glucagon-like peptide 1 (glp-1) receptor modulators and uses thereof in regulating blood glucose levels Download PDFInfo
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- US20150197480A9 US20150197480A9 US14/287,833 US201414287833A US2015197480A9 US 20150197480 A9 US20150197480 A9 US 20150197480A9 US 201414287833 A US201414287833 A US 201414287833A US 2015197480 A9 US2015197480 A9 US 2015197480A9
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/31—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by at least three rings
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- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
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- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/15—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
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- C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/28—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
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Definitions
- Type II diabetes is characterized by decrease in peripheral tissue response to insulin in association with impaired cell function, which results in increase in fasting glycemia (1,2).
- antihyperglycemic drugs such as metformin, sulfonylureas, or thiazolidinediones have been prescribed to promote insulin secretion or enhance insulin sensitivity, these drugs do not target all of the symptoms of type II DM (3,4).
- GLP-1 glucagon-like peptide-1
- GIP gastric inhibitory polypeptide GIP
- pancreatic b cells intestinally derived hormones that stimulate cAMP production via their cognate receptors in pancreatic b cells and subsequently leads to glucose dependent insulin secretion in response to food intake, play an important role in glucose homeostasis (5).
- GLP-1 also preserves pancreatic cells, suppresses glucagon release, reduces hepatic gluconeogenesis, it delays gastric emptying, reduces food intake by promoting satiety and reveals a favorable cardiometabolic profile (6-9).
- GLP-1 also displays extra-pancreatic effects, notably targeting the brain, immune system and heart, where it plays a role in neuroprotection (10-13), regulating immune responses (14-16) and cardioprotection (17-19). All these physiological actions of GLP-1 are mediated via interaction with its cognate G-protein coupled receptor—GLP-1 receptor on the target tissues. However, the exact downstream signaling of these extra-pancreatic physiological actions of GLP-1 still needed further investigation.
- GPCR G protein-coupled receptor signaling machinery was once considered as operating in an one-dimensional way, now has been proved to signal through several distinct mechanisms including those mediated by G proteins and by G-protein independent multifunctional adaptor proteins ⁇ -arrestins.
- G protein-coupled receptor kinases GRKs
- ⁇ -arrestins GRKs and ⁇ -arrestins are considered to be G protein-independent signal transducers (20-22).
- (3-arrestins act as multifunctional scaffolds that interact with many protein partners (23) and protein kinases, thereby leading to the phosphorylation of numerous intracellular targets (24).
- GLP-1 anti-apoptotic effect on pancreatic ⁇ -cells has been shown to be mediated by phosphorylating the pro-apoptotic protein Bad through ⁇ -arrestin1 dependent ERK1/2 activation (30).
- ⁇ -Arrestin1-mediated recruitment of c-Src is involved in proliferative action of GLP-1 on pancreatic ⁇ -cells (31).
- It will be interesting to know other extrapancreatic function of GLP-1 will be also mediated by arrestin coupling and it will be more straightforward to use pathway selective compounds to correlate cellular responses to specific signaling pathway.
- pathway selective compound is rarely available for GLP-1 receptor signaling.
- GLP-1 analogue therapeutics requires frequent subcutaneous administrations, and leads to reduced compliance and high prices in developing area.
- the plasma level of active GLP-1 is around 5 to 10 pM in the basal state, quickly rises to 20 to 50 pM after oral glucose or meal and will slowly declines to basal level over 2 hours (32-34).
- GLP-1 analogue therapeutics usually require to maintain constantly a supra-physiological level of GLP-1 analogues, thus lead to activating GLP-1 receptors constitutively and may cause severe complications upon chronic treatment (35-42).
- GLP-1 receptor modulators e.g., compounds of Formula (I) or (II)
- GLP-1 receptor modulators such as compounds of Formula (I) or (II), or pharmaceutically acceptable salts thereof, and methods of using such compounds for regulating blood glucose levels and/or treating diabetes.
- the GLP-1 receptor modulators described herein are compounds of Formula (I):
- G A is hydrogen, ⁇ O, ⁇ S, —OR′′, —SR′′, —N(R′′) 2 , alkenyl, alkynyl, an amide group, an ester group, a phosphate group, an aldehyde group, a nitrile group, an imino group, a ketone group, a thione group, an isonitrile group, an isothiocyanide group, a carbamate group, a thiocarbamate group, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms, wherein each instance of R′′ is independently hydrogen, a cyclic or acyclic, saturated or unsaturated, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 16 carbon atoms;
- R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 , R A9 , and R A10 are each independently hydrogen, halogen, —OR′′, —N(R′′) 2 , a carboxyl group, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbons, or R A1 and R A2 are joined to form ⁇ O, or R A3 and R A4 are joined to form alkenyl;
- R A11 , R A13 , R A15 , and R A17 are each independently hydrogen, halogen, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms;
- R A12 , R A14 , and R A16 are each independently halogen, —N(R′′) 2 , —SR′′, —OR′′, alkyl, alkenyl, alkynyl, an amide group, a carboxyl group, an ester group, an aldehyde group, a nitrile group, an imino group, a ketone group, a thione group, an isonitrile group, an isothiocyanide group, a urea group, a carbamate group, or a thiocarbamate group, or R A14 and R A15 are joined to form ⁇ O or ⁇ S;
- R A20 is hydrogen, halogen, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms;
- R A21 is hydrogen, halogen, —N(R′′) 2 , —SR′′, —OR′′, —CH 2 OR′′, alkenyl, alkynyl, an amide group, a carboxyl group, an ester group, an aldehyde group, a nitrile group, an imino group, a ketone group, a thione group, an isonitrile group, an isothiocyanide group, a carbamate group, a thiocarbamate group, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms.
- the salts can be formed between a positively charged substituent (e.g., amino) on a compound and an anion.
- Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate.
- a negatively charged substituent (e.g., carboxylate) on a compound can form a salt with a cation.
- Suitable cations include, but are not limited to, sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as teteramethylammonium ion.
- a salt described herein is a pharmaceutically acceptable salt.
- pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g., a human or non-human animal) without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
- Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases.
- a pharmaceutically acceptable salt can be a salt described herein.
- Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
- the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
- Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
- HPLC high pressure liquid chromatography
- a moiety described herein may be unsubstituted or may be substituted (e.g., at least one hydrogen atom of the moiety being replaced with a non-hydrogen atom or group).
- the group may be substituted, as valency permits, with one or more substituents independently selected from the group consisting of C 1-6 alkyl (e.g., unsubstituted C 1-6 alkyl (e.g., methyl, ethyl, propyl, or butyl) or substituted C 1-6 alkyl (e.g., —CF 3 , —CH 2 —CF 3 , or —C 2 F 5 )), —OR a1 (e.g., —OH, —OMe, or —OEt), —N(R a1 ) 2 (e.g., —NH 2 , —NHMe, or —NMe 2 ), —SR a1 (e
- C 1-6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.
- (hetero)aliphatic refers to aliphatic or heteroaliphatic.
- aliphatic refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.
- heteroaliphatic refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
- alkyl refers to a radical of a straight-chained (“unbranched”) or branched, saturated, hydrocarbon group.
- an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”).
- C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ).
- alkenyl refers to a radical of a straight-chained or branched hydrocarbon group having one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2-6 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
- C 2-6 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), and hexenyl (C 6 ).
- alkynyl refers to a radical of a straight-chained or branched hydrocarbon group having one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds).
- an alkynyl group has 2 to 6 carbon atoms (“C 2-6 alkynyl”).
- the one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
- C 2-6 alkynyl groups include ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), pentynyl (C 5 ), and hexynyl (C 6 ).
- Heteroalkyl refers to an alkyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
- a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-16 alkyl”).
- a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-6 alkyl”).
- a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-3 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted or substituted with one or more substituents.
- Heteroalkenyl refers to an alkenyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
- a heteroalkenyl group has 2 to 16 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-16 alkenyl”).
- a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-6 alkenyl”).
- a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-3 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted or substituted with one or more substituents.
- Heteroalkynyl refers to an alkynyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
- a heteroalkynyl group has 2 to 16 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-16 alkynyl”).
- a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-3 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted or substituted with one or more substituents.
- Carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C 3-10 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system.
- a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”).
- a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”).
- a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”).
- a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”).
- Exemplary C 3-6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
- Exemplary C 3-8 carbocyclyl groups include, without limitation, the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
- Exemplary C 3-10 carbocyclyl groups include, without limitation, the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 1-10 ), cyclodecenyl (C 1-10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 1-10 ), spiro[4.5]decanyl (C 1-10 ), and the like.
- the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged.
- Carbocyclyl can be saturated, and saturated carbocyclyl is referred to as “cycloalkyl.”
- carbocyclyl is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C 3-10 cycloalkyl”).
- a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3-8 cycloalkyl”).
- a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-4 cycloalkyl”).
- a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10 cycloalkyl”). Examples of C 5-4 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ). Examples of C 3-4 cycloalkyl groups include the aforementioned C 54 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
- C 3-8 cycloalkyl groups include the aforementioned C 3-4 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
- each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
- the cycloalkyl group is unsubstituted C 3-10 cycloalkyl.
- the cycloalkyl group is substituted C 3-10 cycloalkyl.
- Carbocyclyl can be partially unsaturated.
- Carbocyclyl including one or more C ⁇ C double bond in the carbocyclic ring is referred to as “cycloalkenyl.”
- Carbocyclyl including one or more C ⁇ C triple bond in the carbocyclic ring is referred to as “cycloalkynyl.”
- Carbocyclyl includes aryl. “Carbocyclyl” also includes ring systems wherein the carbocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclic ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
- each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
- the carbocyclyl group is unsubstituted C 3-10 carbocyclyl.
- the carbocyclyl group is substituted C 3-10 carbocyclyl.
- Heterocyclyl refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”).
- the point of attachment can be a carbon or nitrogen atom, as valency permits.
- a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system, such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated (“heterocycloalkyl”) or can be partially unsaturated.
- Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
- Heterocyclyl includes heteroaryl.
- Heterocyclyl also includes ring systems wherein the heterocyclic ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclic ring, or ring systems wherein the heterocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclic ring system.
- each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
- the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.
- a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”).
- a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”).
- a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”).
- the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
- the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
- the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
- Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
- Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
- Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione.
- Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
- Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
- Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
- Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
- Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazinanyl.
- Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
- Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
- Exemplary 5-membered heterocyclyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
- Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
- Aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
- an aryl group has six ring carbon atoms (“C 6 aryl”; e.g., phenyl).
- an aryl group has ten ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
- an aryl group has fourteen ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
- Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
- each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
- the aryl group is unsubstituted C 6-14 aryl.
- the aryl group is substituted C 6-14 aryl.
- Alkyl is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group. In certain embodiments, the aralkyl is optionally substituted benzyl. In certain embodiments, the aralkyl is benzyl. In certain embodiments, the aralkyl is optionally substituted phenethyl. In certain embodiments, the aralkyl is phenethyl.
- Alkenyl is a subset of alkenyl and aryl, as defined herein, and refers to an optionally substituted alkenyl group substituted by an optionally substituted aryl group.
- An example of aralkenyl is styrenyl (i.e., —CH ⁇ CHPh).
- Alkynyl is a subset of alkynyl and aryl, as defined herein, and refers to an optionally substituted alkynyl group substituted by an optionally substituted aryl group.
- Heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”).
- heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
- Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
- Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
- Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
- the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
- a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”).
- a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”).
- a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
- the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
- the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
- the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
- each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.
- the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.
- Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
- Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
- Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
- Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
- Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
- Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
- Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
- Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
- Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
- Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
- oxo refers to the a moiety of the formula: ⁇ O.
- amide or “amide group” refers to a moiety of the formula: —N(R pp )C( ⁇ O)R qq , wherein R pp is a nitrogen atom substituent described herein, and R qq is a carbon atom substituent described herein.
- esters or “ester group” refers to a moiety of the formula: —C( ⁇ O)OR rr or —OC( ⁇ O)R rr , wherein R rr is an oxygen atom substituent described herein.
- phosphate or “phosphate group” refers to a moiety of the formula: —OP( ⁇ O)(OR oo ) 2 , wherein each instance of R oo is independently an oxygen atom substituent described herein or a cationic counterion.
- carboxyl or “carboxyl group” refers to a moiety of the formula: —C( ⁇ O)OH.
- aldehyde or “aldehyde group” refers to a moiety of the formula: —C( ⁇ O)H.
- thialdehyde or “thialdehyde group” refers to a moiety of the formula: —C( ⁇ S)H.
- nitrile or “nitrile group” refers to a moiety of the formula: —CN or -L-CN, wherein L is substituted or unsubstituted, branched or unbranched, C 1-16 alkylene; substituted or unsubstituted, branched or unbranched, C 2-16 alkenylene; or substituted or unsubstituted, branched or unbranched, C 2-16 alkynylene.
- hydroxyl refers to the group —OH.
- substituted hydroxyl or “substituted hydroxyl” refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from —OR aa , —ON(R bb ) 2 , —OC( ⁇ O)SR aa , —OC( ⁇ O)R aa , —OCO 2 R aa , —OC( ⁇ O)N(R bb ) 2 , —OC( ⁇ NR bb )R aa , —OC( ⁇ NR bb )OR aa , —OC( ⁇ NR bb )N(R bb ) 2 , —OS( ⁇ O)R aa , —OSO 2 R aa , —OSi(R a
- amino refers to a moiety of the formula: —N(R ii ) 2 , wherein each instance of R ii is independently a nitrogen atom substituent described herein, or two instances of R ii are connected to form substituted or unsubstituted heterocyclyl.
- the amino is unsubstituted amino (i.e., —NH 2 ).
- the amino is a substituted amino group, wherein at least one instance of R ii is not hydrogen.
- amino or “imino group” refers to a moiety of the formula: ⁇ NR ss , wherein R ss is a nitrogen atom substituent described herein.
- ketone or “ketone group” refers to a moiety of the formula: —C( ⁇ O)R tt , wherein R tt is a carbon atom substituent described herein.
- thione or “thione group” refers to a moiety of the formula: —C( ⁇ S)R uu , wherein R uu is a carbon atom substituent described herein.
- isonitrile or “isonitrile group” refers to a moiety of the formula: —NC.
- isothiocyanide or “isothiocyanide group” refers to a moiety of the formula: —SNC.
- thioate or “thioate group” refers to a moiety of the formula: —C( ⁇ O)SR zz or —C( ⁇ S)OR jj , wherein R zz is a sulfur atom substituent described herein, and R is an oxygen atom substituent described herein.
- thioamide or “thioamide group” refers to a moiety of the formula: —N(R mm )C( ⁇ S)R nn , wherein R mm is a nitrogen atom substituent described herein, and R nn is a carbon atom substituent described herein.
- dithioate or “dithioate group” refers to a moiety of the formula: —C( ⁇ S)SR kk , wherein R kk is a sulfur atom substituent described herein.
- isocyanato or “isocyanato group” refers to a moiety of the formula: —NCO.
- isothiocyanato or “isothiocyanato group” refers to a moiety of the formula: —NCS.
- carboxylate refers to a moiety of the formula: —N(R vv )C( ⁇ O)OR ww or —OC( ⁇ O)N(R vv ) 2 , wherein each instance of R vv is independently a nitrogen atom substituent described herein, and R ww is an oxygen atom substituent described herein.
- urea or “urea group” refers to a moiety of the formula: —N(R zl )C( ⁇ O)N(R zl ) 2 , wherein each instance of R zl is independently a nitrogen atom substituent described herein.
- thiocarbamate or “thiocarbamate group” refers to a moiety of the formula: —N(R vv )C( ⁇ S)OR ww or —OC( ⁇ S)N(R vv ) 2 , —N(R vv )C( ⁇ O)SR yy or —SC( ⁇ O)N(R vv ) 2 , wherein each instance of R vv is independently a nitrogen atom substituent described herein, R ww is an oxygen atom substituent described herein, and R yy is a sulfur atom substituent described herein.
- Halo or halogen refers to fluorine (fluoro, F), chlorine (chloro or Cl), bromine (bromo or Br), or iodine (iodo or I).
- atom, moiety, or group described herein may be unsubstituted or substituted, as valency permits, unless otherwise expressly provided.
- substituted refers to that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
- a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
- substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
- the present disclosure contemplates any and all such combinations in order to arrive at a stable compound.
- heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
- the substituent is a carbon atom substituent. In certain embodiments, the substituent is a nitrogen atom substituent. In certain embodiments, the substituent is an oxygen atom substituent. In certain embodiments, the substituent is a sulfur atom substituent. In certain embodiments, a substituent may contribute to optical isomerism and/or stereo isomerism of a compound.
- Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , —ON(R bb ) 2 , —N(R bb ) 2 , —N(R bb ) 3 + X ⁇ , —N(OR cc )R bb , —SH, —SR aa , —SSR cc , —C( ⁇ O)R aa , —CO 2 H, —CHO, —C(OR cc ) 2 , —CO 2 R aa , —OC( ⁇ O)R aa , —OCO 2 R aa , —C( ⁇ O)N(R bb ) 2 , —OC( ⁇ O)N(R bb ) 2 , —NR bb C
- each instance of R aa is, independently, selected from C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
- each instance of R bb is, independently, selected from hydrogen, —OH, —OR aa , —N(R cc ) 2 , —CN, —C( ⁇ O)R aa , —C( ⁇ O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C( ⁇ NR cc )OR aa , —C( ⁇ NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C( ⁇ S)N(R cc ) 2 , —C( ⁇ O)SR cc , —C( ⁇ S)SR cc , —P( ⁇ O) 2 R aa , —P( ⁇ O)(R aa ) 2 ,
- each instance of R cc is, independently, selected from hydrogen, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; each instance of R dd is, independently, selected from halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR ee , —ON(R ff ) 2 , —N(R ff )
- each instance of R ee is, independently, selected from C 1-6 alkyl, C 14 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
- each instance of R ff is, independently, selected from hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; and
- each instance of R gg is, independently, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OC 1-6 alkyl, —ON(C 1-6 alkyl) 2 , —N(C 1-6 alkyl) 2 , —N(C 1-6 alkyl) 3 + X ⁇ , —NH(C 1-6 alkyl) 2 + X ⁇ , —NH 2 (C 1-6 alkyl) + X ⁇ , —NH 3 + X ⁇ , —N(OC 1 alkyl)(C 1-6 alkyl), —N(OH)(C 1-6 alkyl), —NH(OH), —SH, —SC 1-6 alkyl, —SS(C 1-6 alkyl), —C( ⁇ O)(C 1-6 alkyl), —CO 2 H, —CO 2 (C 1-6 alkyl), —OC( ⁇ O)(
- a “counterion” or “anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality.
- exemplary counterions include halide ions (e.g., F ⁇ , Cl ⁇ , Br ⁇ , I ⁇ ), NO 3 ⁇ , ClO 4 ⁇ , OH ⁇ , H 2 PO 4 ⁇ , HSO 4 ⁇ , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate,
- Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.
- Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, —OH, —OR aa , —N(R cc ) 2 , —CN, —C( ⁇ O)R aa , —C( ⁇ O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C( ⁇ NR bb )R aa , —C( ⁇ NR cc )OR aa , —C( ⁇ NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C( ⁇ S)N(R
- the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group).
- Nitrogen protecting groups include, but are not limited to, —OH, —OR aa , —N(R cc ) 2 , —C( ⁇ O)R aa , —C( ⁇ O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C( ⁇ NR cc )R aa , —C( ⁇ NR cc )OR aa , —C( ⁇ NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C( ⁇ S)N(R cc ) 2 , —C( ⁇ O)SR cc , —C(C(
- Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis , T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
- nitrogen protecting groups include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide,
- Nitrogen protecting groups also include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate
- Nitrogen protecting groups further include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), ⁇ -trimethylsilylethanesulfonamide (SES), 9-an
- nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacyl derivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4
- oxygen atom substituents include, but are not limited to, —R aa , —C( ⁇ O)SR aa , —C( ⁇ O)R aa , —CO 2 R aa , —C( ⁇ O)N(R bb ) 2 , —C( ⁇ NR bb )R aa , —C( ⁇ NR bb )OR aa , —C( ⁇ NR bb )N(R bb ) 2 , —S( ⁇ O)R aa , —SO 2 R aa , —Si(R aa ) 3 , —P(R cc ) 2 , —P(R cc ) 3 , —P( ⁇ O) 2 R aa , —P( ⁇ O)(R aa ) 2 , —P( ⁇ O)(OR cc ) 2 , —P( ⁇ O) 2 N(
- the oxygen atom substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group).
- Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis , T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
- oxygen protecting groups include, but are not limited to, methyl, t-butyloxycarbonyl (BOC or Boc), methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-me
- Exemplary sulfur atom substituents include, but are not limited to, —R aa , —C( ⁇ O)SR aa , —C( ⁇ O)R aa , —CO 2 R aa , —C( ⁇ O)N(R bb ) 2 , —C( ⁇ NR bb )R aa , —C( ⁇ NR bb )OR aa , —C( ⁇ NR bb )N(R bb ) 2 , —S( ⁇ O)R aa , —SO 2 R aa , —Si(R aa ) 3 , —P(R cc ) 2 , —P(R cc ) 3 , —P( ⁇ O) 2 R aa , —P( ⁇ O)(R aa ) 2 , —P( ⁇ O)(OR cc ) 2 , —P( ⁇ O) 2 N
- the sulfur atom substituent present on a sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group).
- Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis , T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
- G A can be hydrogen, ⁇ O, ⁇ S, —OR′′, —SR′′, —NR′′H, alkenyl, alkynyl, an amide group, an ester group, an aldehyde group, a nitrile group, an imino group, a ketone group, a thione group, an isonitrile group, an isothiocyanide group, a carbamate group, a thiocarbamate group, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms, wherein each instance of R′′ can be independently hydrogen, a cyclic or acyclic, saturated or unsaturated, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 16 carbon atoms;
- R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 , R A9 , and R A10 can each independently be hydrogen, halogen, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbons;
- R A11 , R A12 , R A13 , R A15 , R A16 , and R A17 can each independently be hydrogen, halogen, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms;
- R A14 can be halogen, —NR′′H, —SR′′, —OR′′, alkenyl, alkynyl, an amide group, an ester group, an aldehyde group, a nitrile group, an imino group, a ketone group, a thione group, an isonitrile group, an isothiocyanide group, a carbamate group, or a thiocarbamate group;
- R A20 can be hydrogen, halogen, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms;
- R A21 can be hydrogen, halogen, —NR′′H, —SR′′, —OR′′, alkenyl, alkynyl, an amide group, an ester group, an aldehyde group, a nitrile group, an imino group, a ketone group, a thione group, an isonitrile group, an isothiocyanide group, a carbamate group, a thiocarbamate group, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms.
- a compound of Formula (I) can be of Formula (I-A):
- a compound of Formula (I) can be of the formula:
- a compound of Formula (I) can be of Formula (I-B):
- a compound of Formula (I) can be of Formula (I-C):
- a compound of Formula (I) can be of Formula (I-D):
- G A can be hydrogen. In certain embodiments, G A can be ⁇ O, ⁇ S, —SR′′, —OR′′, —N(R′′) 2 , —OH, —SH, or —NH 2 . In certain embodiments, G A can be can be ⁇ O. In certain embodiments, G A can be —OR′′ (e.g., —OH, —O(substituted or unsubstituted C 1-6 alkyl), or —OC( ⁇ O)(substituted or unsubstituted C 1-6 alkyl)). In certain embodiments, G A can be can be ⁇ S. In certain embodiments, G A can be —SR′′ (e.g., —SH).
- G A can be —N(R′′) 2 , —NHR′′ (such as —NH(substituted or unsubstituted C 1-6 alkyl) or —NHC( ⁇ O)(substituted or unsubstituted C 1-6 alkyl)), or —NH 2 .
- G A can be can be alkenyl (e.g., acyclic, substituted or unsubstituted, C 1-6 alkenyl, such as ⁇ CHC( ⁇ O)O(substituted or unsubstituted C 1-6 alkyl)).
- G A can be can be a phosphate group (e.g., —OP( ⁇ O)(acyclic, substituted or unsubstituted, C 1-6 alkyl) 2 ).
- R A1 can be hydrogen.
- R A1 can be halogen.
- R A1 can be an acyclic, substituted or unsubstituted, branched or unbranched, aliphatic group having 1 to 6 carbons (e.g., acyclic, substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (such as —CF 3 )).
- R A1 can be —OR′′ (e.g., —OH). In certain embodiments, R A1 can be —N(R′′) 2 (e.g., —NMe 2 ). In certain embodiments, R A2 can be hydrogen. In certain embodiments, R A1 and R A2 can be joined to form ⁇ O. In certain embodiments, R A3 can be hydrogen.
- R A3 can be acyclic, substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (e.g., methyl, —CF 3 , —CH 2 Br, —CH 2 OH, —CH 2 OC( ⁇ O)(substituted or unsubstituted C 1-6 alkyl), or ethyl).
- R A3 can be carboxyl.
- R A4 can be hydrogen.
- R A4 can be acyclic, substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (e.g., methyl, —CF 3 , —CH 2 C( ⁇ O)(substituted or unsubstituted C 1-6 alkyl), or ethyl).
- R A3 and R A4 can be joined to form alkenyl (e.g., ⁇ CH 2 ).
- R A5 can be hydrogen.
- R A5 can be acyclic, substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (e.g., methyl or —CH 2 OCF 3 ).
- R A5 cannot be hydrogen.
- R A6 can be acyclic, substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (e.g., methyl, ethyl, —CH 2 OH, —CH 2 C( ⁇ O)Me, or —CH 2 C( ⁇ S)Me).
- R A6 cannot be —CH 3 .
- R A7 can be hydrogen.
- R A7 can be acyclic, substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (e.g., methyl).
- R A7 can be —OR′′ (e.g., —OH).
- R A8 can be hydrogen.
- R A8 can be acyclic, substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (e.g., methyl).
- at least one of R A7 and R A8 cannot be hydrogen.
- R A9 can be hydrogen.
- R A9 can be acyclic, substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (e.g., methyl).
- R A10 can be hydrogen.
- R A9 and R A10 cannot be hydrogen.
- R A11 can be hydrogen.
- R A12 can be hydrogen.
- R A12 can be an amino group (e.g., —N(R′′) 2 , —NHR′′, or —NH 2 ).
- R A13 is absent. In certain embodiments, at least one of R A12 and R A13 cannot be hydrogen.
- R A14 can be halogen, —NR′′H, —SR′′, —OR′′, alkenyl, alkynyl, an amide group, a carboxyl group, an ester group, an aldehyde group, a nitrile group, an imino group, a ketone group, a thione group, an isonitrile group, an isothiocyanide group, a carbamate group, or a thiocarbamate group.
- R A14 can be hydrogen.
- R A14 can be alkyl (e.g., acyclic, substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (e.g., —CH 2 CF 3 , —CH 2 OR′′ (such as —CH 2 OH), —CH 2 SR′′ (such as —CH 2 SH), —CH 2 N(R′′) 2 (such as —CH 2 NHMe or —CH 2 NH 2 ), —CH 2 C( ⁇ O)(acyclic, substituted or unsubstituted, branched or unbranched, C 1-20 aliphatic (such as
- R A14 cannot be —CH 2 OH.
- R A14 can be a carboxyl group.
- R A14 can be an ester group (e.g., —C( ⁇ O)O(acyclic, substituted or unsubstituted, branched or unbranched, C 1-6 alkyl), such as —C( ⁇ O)OMe).
- R A14 can be an aldehyde group.
- R A14 can be a ketone group (e.g., —C( ⁇ O)-(acyclic, substituted or unsubstituted, branched or unbranched, C 1-6 alkyl), such as —C( ⁇ O)Me).
- R A14 can be a urea group (e.g., —NHC( ⁇ O)—NH(substituted or unsubstituted phenyl), such as —NHC( ⁇ O)—NHPh).
- R A15 can be absent.
- R A14 and R A15 can be joined to form ⁇ O or ⁇ S.
- R A16 can be hydrogen.
- R A16 can be a carbamate group (e.g., —NHC( ⁇ O)O(acyclic, substituted or unsubstituted, branched or unbranched, C 1-6 alkyl), such as —NHC( ⁇ O)OEt).
- R A17 can be hydrogen. In certain embodiments, at least one of R A16 and R A17 cannot be hydrogen.
- R A20 can be hydrogen. In certain embodiments, R A20 can be absent. In certain embodiments, R A21 can be hydrogen.
- R A21 can be a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms.
- R A21 can be acyclic, substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (e.g., —CH 2 OR′′ (such as —CH 2 OH, —CH 2 C( ⁇ O)OMe, or —CH 2 C( ⁇ O)(acyclic, substituted or unsubstituted, branched or unbranched, C 1-20 aliphatic (such as
- R A21 can be acyclic, substituted or unsubstituted, branched or unbranched, C 2-6 alkenyl (e.g., —CH ⁇ CHCH 3 or —CH ⁇ NBn).
- R A21 can be an aldehyde group.
- R A21 can be a carboxyl group.
- each instance of R′′ can independently be hydrogen. In certain embodiments, each instance of R′′ can independently be acyclic, substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (e.g., methyl, ethyl, propyl, or butyl).
- the tricyclic ring system of Formula (I) may include substituents in addition to one or more of R A1 to R A17 , R A20 to R A21 , and G A , as valency permits.
- the tricyclic ring system of Formula (I) can further be substituted at one or two of the positions marked with “*”:
- the tricyclic ring system of Formula (I) can further be substituted with one or more substituents independently selected from the group consisting of halogen; substituted and unsubstituted C 1-6 aliphatic (e.g., unsubstituted C 1-6 alkyl, such as —CH 3 ); and —OR′′ (e.g., —OH).
- substituents independently selected from the group consisting of halogen; substituted and unsubstituted C 1-6 aliphatic (e.g., unsubstituted C 1-6 alkyl, such as —CH 3 ); and —OR′′ (e.g., —OH).
- At least one of R A1 , R A2 , R A5 , R A7 , R A8 , R A9 , R A10 , R A11 , R A12 , R A13 , R A15 , R A16 , and R A17 cannot be hydrogen.
- at least one of R A3 , R A4 , and R A6 cannot be —CH 3 .
- R A21 is —CHO and G A is —OH or ⁇ O, each of R A14 and R A15 cannot be —CHO.
- the compound of Formula (I) cannot be of the formula:
- G A is —OR′′ or —N(R′′) 2 ;
- R A14 is an amide group, a nitrile group, an ester group, or substituted methyl
- R A21 is an aldehyde group, —CH 2 OR′′, or an ester group.
- GLP-1 receptor modulators described herein are compounds of Formula (II):
- G is hydrogen, ⁇ O, ⁇ S, —NR′H, —SR′, or —OR′, wherein R′ is hydrogen, an ester group, a ketone group, a thione group, or a cyclic or acyclic, saturated or unsaturated, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 16 carbon atoms;
- W is —O—, —S— or —NR′—;
- X and Y are each independently a single bond or a saturated or unsaturated, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 3 carbon atoms;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 12 and R 13 are each independently hydrogen, halogen, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms, or R 2 and R 3 may join to form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- R 10 and R 11 are each independently hydrogen, halogen, an amino group, an amide group, an ester group, an aldehyde group, a nitrile, an imino group, a ketone group, a thione group, an isonitrile group, an isothiocyanide group, a carbamate group, a thiocarbamate group, or a cyclic or acyclic, saturated or unsaturated, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms;
- R 14 is hydrogen or a saturated or unsaturated, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1-16 carbon atoms;
- R 15 is hydrogen or a saturated or unsaturated, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1-6 carbon atoms;
- X and Y can each be methylene; R 1 can be methyl; R 2 , R 3 and the two carbon atoms directly bonded therewith can form a 3,3-dimethyl cyclohexane ring;
- R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , and R 13 can each be hydrogen;
- R 11 can be an amide group, an acid group, an ester group, an aldehyde group, an alcohol group, a carbamate group, a thiocarbamate, a carbonate, a nitrile group, an amino group, or an imino group; and the bond between the two carbon atoms directly bonded with R 10 and R 11 can be a double bond.
- X and Y can each be methylene;
- R 1 can be methyl;
- R 2 , R 3 and the two carbon atoms directly bonded therewith can form a 3,3-dimethyl cyclohexane ring;
- R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , and R 13 can each be hydrogen;
- R 11 can be an amide group, an acid group, an ester group, an aldehyde group, an alcohol group, a carbamate group, a thiocarbamate, a carbonate, a nitrile group, an amino group, or an imino group;
- W can be —O—;
- R 12 , R 13 , R 14 , and R 15 can each be hydrogen;
- G can be ⁇ O; and the bond between the two carbon atoms directly bonded with R 10 and R 11 can be a double bond.
- a compound of Formula (II) can be of Formula (II-A):
- a compound of Formula (II) can be of Formula (II-B):
- a compound of Formula (II) can be of Formula (II-C):
- a compound of Formula (II) can be of Formula (II-D):
- G can be can be ⁇ O.
- G can be —OR′ (e.g., —OH, —O(substituted or unsubstituted C 1-6 alkyl), or —OC( ⁇ O)(substituted or unsubstituted C 1-6 alkyl)).
- G can be can be ⁇ S.
- G can be —SR′ (e.g., —SH or —S(substituted or unsubstituted C 1-6 alkyl)).
- G can be —NHR′ (such as —NH(substituted or unsubstituted C 1-6 alkyl) or —NHC( ⁇ O)(substituted or unsubstituted C 1-6 alkyl)) or —NH 2 .
- W can be —O—.
- W can be —S—.
- W can be —NR′— (e.g., —N(substituted or unsubstituted C 1-6 alkyl)- or —NH—).
- X can be methylene.
- X can be ethanediyl, vinylene bridge, or propanediyl.
- Y can be methylene.
- Y can be ethanediyl, vinylene bridge, or propanediyl.
- R 1 can be substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (e.g., methyl, —CH 2 OH, —CH 2 C( ⁇ O)Me, or —CH 2 C( ⁇ S)Me).
- R 1 cannot be —CH 3 .
- R 2 , R 3 , and the two carbon atoms directly bonded therewith form cycloalkyl (e.g., a 3,3-dimethyl cyclohexane ring
- R 2 , R 3 , and the two carbon atoms directly bonded therewith cannot form
- R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , and R 13 can each be hydrogen.
- R 4 can be hydrogen.
- R 4 can be substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (e.g., methyl or —CH 2 OCF 3 ).
- R 4 cannot be hydrogen.
- R 5 can be hydrogen.
- R 5 can be substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (e.g., methyl).
- R 5 can be —OR′ (e.g., —OH).
- R 6 can be hydrogen.
- R 6 can be substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (e.g., methyl).
- at least one of R 5 and R 6 cannot be hydrogen.
- R 7 can be hydrogen.
- R 7 can be substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (e.g., methyl).
- R 8 can be hydrogen.
- at least one of R 7 and R 8 cannot be hydrogen.
- R 9 can be hydrogen.
- R 10 can be hydrogen.
- R 10 can be an amino group (e.g., —N(R′) 2 , —NHR′, or —NH 2 ).
- R 11 can be hydrogen.
- R 11 can be an amide group, an ester group, an aldehyde group, a carbamate group, a thiocarbamate, a nitrile group, an amino group, an imino group, or substituted or unsubstituted, branched or unbranched, C 1-6 alkyl.
- R 11 can be an ester group, an aldehyde group, a ketone group, or substituted or unsubstituted, branched or unbranched, C 1-6 alkyl.
- R 11 can be substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (e.g., —CH 2 CF 3 , —CH 2 OR′ (such as —CH 2 OH), —CH 2 SR′ (such as —CH 2 SH), —CH 2 N(R′) 2 (such as —CH 2 NHMe or —CH 2 NH 2 ), or —CH 2 C( ⁇ O)N(R′) 2 (such as —CH 2 C( ⁇ O)NH(substituted or unsubstituted C 1-6 alkyl))).
- R 11 cannot be —CH 2 OH.
- R 11 can be an ester group (e.g., —C( ⁇ O)O(substituted or unsubstituted, branched or unbranched, C 1-6 alkyl), such as —C( ⁇ O)OMe).
- R 11 can be an aldehyde group.
- R 11 can be a ketone group (e.g., —C( ⁇ O)-(substituted or unsubstituted, branched or unbranched, C 1-6 alkyl), such as —C( ⁇ O)Me).
- R 12 can be hydrogen.
- R 13 can be hydrogen.
- R 14 can be hydrogen.
- R 14 can be substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (e.g., —C( ⁇ O)OMe or —C( ⁇ O) (substituted or unsubstituted, C 2-20 alkenyl).
- R 21 can be
- R 21 can be —CH 2 OH. In certain embodiments, R 21 can be an aldehyde group. In certain embodiments, R 15 can be hydrogen. In certain embodiments, R 15 can be absent. In certain embodiments, the bond between the two carbon atoms directly bonded with R 10 and R 11 can be a double bond. In certain embodiments, the bond between the two carbon atoms directly bonded with R 10 and R 11 can be a single bond. In certain embodiments, R′ can be hydrogen. In certain embodiments, R′ can be substituted or unsubstituted, branched or unbranched, C 1-6 alkyl (e.g., methyl, ethyl, propyl, or butyl).
- R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 cannot be hydrogen.
- R 1 cannot be —CH 3 .
- R 21 when R 21 is —CHO and G is —OH or ⁇ O, R 11 cannot be —CHO.
- the compound of Formula (II) cannot be of the formula:
- G is —OR′ or —NR′H
- R 11 is an amide group, a nitrile, an ester group, or substituted methyl
- R 21 is an aldehyde group or —CH 2 OR 14 .
- a compound described herein cannot be of the formula:
- a compound described herein cannot be of the formula:
- R x is a phosphorous-containing group.
- Exemplary compounds described herein include, but are not limited to:
- compositions including one or more of the GLP-1 receptor modulators described herein and a pharmaceutically acceptable carrier.
- this present disclosure features methods for regulating blood glucose level and/or treating diabetes in a subject.
- the method comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition described herein.
- the subject is a human (e.g., a human patient having, at risk for, or suspected of having diabetes, e.g., type I or type II diabetes.
- this present disclosure features methods of treating diabetes in a subject, the method including administering to a subject in need thereof an effective amount (e.g., a therapeutically effective amount) of a pharmaceutical composition described herein.
- an effective amount e.g., a therapeutically effective amount
- the methods described above can also include the step of identifying a subject in need of the treatment, e.g., a human patient having or at risk for developing abnormal blood glucose levels or any disorder associated therewith.
- kits comprising a pharmaceutical composition described herein and optionally, instructions for using the kits.
- a pharmaceutical composition as described herein for use in regulating blood glucose level and/or treating diabetes in a subject, and the use of such a pharmaceutical composition for the manufacture of a medicament for regulating blood glucose level and/or treating diabetes in a subject.
- FIG. 1 is a chart showing the effect of GLP-1 (7-36) on endocytosis medicated by GLP-1 receptor.
- the GLP-1R/ ⁇ -arrestin2 GFP double stable expression U2OS cells were plated in 384-well plastic plates at a density of 3000 cell/well and cultured overnight. Wells were treated with vehicle or various concentrations of GLP-1(7-36) for 60 min at room temperature in the presence ( ⁇ ) or absence ( ⁇ ) of 1 ⁇ M of exendin 9.
- FIG. 2 shows the activity of an ethanol extract of Hedychium coronarium (HC) in potentiating the GLP-1 activity.
- HC Hedychium coronarium
- FIG. 3 includes charts showing normal phase silica gel chromatograms of HC ethyl acetate partition fraction.
- 7 g of EtOAc partition material was subjected to normal phase silica gel chromatography and resolved into 37 fractions.
- the activity was assayed for each fraction (the ability of 0.002 mg/ml partially purified compounds to potentiate the receptor endocytosis elicited by 4 nM of GLP-1) and expressed as % of the maximal activity elicited by 1 ⁇ M of GLP-1.
- ⁇ represents weight of each fraction.
- ⁇ indicates the activity of each fraction.
- I is the pooled fraction 5 to fraction 12.
- FIG. 4 shows an exemplary fractionation of I (the pooled fraction 5 to fraction 12) on a KROMASIL C 18 column.
- I the pooled fraction 5 to fraction 12
- a KROMASIL C 18 column 250 ⁇ 50 mm, 10 ⁇ m
- Weight of each fraction ( ⁇ ) and ( ⁇ ) indicates activity of each fraction.
- FIG. 5 shows exemplary results of a dose response analysis of galanal B on GLP-1 (Panel A) or PTH (Panel B) induced receptor endocytosis.
- the GLP-1R/3-arrestin2 GFP (Panel A) or PTHR/ ⁇ -arrestin 2 GFP (Panel B) double stable expression U2OS cells were plated in 384-well plastic plates at a density of 3000 cell/well and cultured overnight.
- Panel C shows exemplary results of a dose response data of GLP-1 from 0.15 nM to 324 nM on GLP-1 receptor activation in the presence ( ⁇ ) or absence ( ⁇ ) of 0.001 mg/ml of galanal B.
- FIG. 6 shows that galanal B potentiated GLP-1 elicited GLP-1 receptor endocytosis.
- FIG. 7 shows that galanal B, compound 1, and compound 2 increased the potency of GLP-1 dependent receptor endocytosis.
- FIG. 8 shows that exendin 9 diminished positive modulation effect compound 1, compound 2, and galanal B on GLP-1 elicited GLP-1 receptor endocytosis.
- Panel A Titration of GLP-1 on GLP-1 receptor endocytosis in the presence of 0.0001 mg/ml of galanal B ( ⁇ ), absence of galanal B ( ⁇ ), and in the presence of 0.0001 mg/ml of galanal B plus 1.8 mM of Exendin 9 ( ⁇ ).
- FIG. 9 shows that compound 1 suppressed, and compound 2 potentiated, GLP-1 dependent cAMP production in RINm5F cells
- Panel A Dose response titration of GLP-1 in the presence of 0.003 mg/ml of galanal B ( ⁇ ), compound 2 ( ⁇ ), compound 1 ( ⁇ ), or GLP-1 alone ( ⁇ ).
- Panel B Dose response of galanal ( ⁇ ) or compound 2 ( ⁇ ) on cAMP production in RINm5F cells stimulated by 3 nM of GLP-1.
- Panel C Dose response of compound 1 ( ⁇ ) on cAMP production in RINm5F cells elicited by 60 nM of GLP-1.
- FIG. 10 shows that potentiation effect of compound 2 on GLP-1 elicited cAMP generation is blocked by exendin 9 and MDL 12330A.
- Panel A Titration of exendin 9 on cAMP production in RINm5F cells stimulated by 2 nM of GLP-1 in the presence ( ⁇ ) and absence ( ⁇ ) of 0.0025 mg/ml of compound 2.
- Panel B Titration of GLP-1 on cAMP production in RIMm5F cells ( ⁇ ) or in the presence of 0.0025 mg/ml of compound 2 (a) or in the presence of 0.0025 mg/ml of compound 2 plus 250 mM of MDL 12330A (b).
- FIG. 11 shows the effect of compound 1 and compound 2 on cAMP production in RINm5F cells elicited by GIP and Glucagon.
- Panel A Titration of GIP on the production of cAMP from RINm5F cells ( ⁇ ) or in the presence of 0.025 mg/ml of compound 2 ( ⁇ ) or compound 1 ( ⁇ ).
- Panel B Titration of glucagon on the production of cAMP from RINm5F cells ( ⁇ ) or in the presence of 0.025 mg/ml of compound 2 ( ⁇ ) or compound 1 ( ⁇ ).
- GLP-1 therapeutics for diabetes (e.g., type II diabetes) and compounds that selectively regulates the GLP-1 pathway
- edible plants were screened for activities that modulate the GLP-1 receptor signaling.
- plant extracts were screened to identify components that positively modulate GLP-1 receptor signaling in a GLP-1 dependent manner.
- the compounds identified in the screening process do not act merely in an on-and-off manner, as those GLP-1 therapies known in the art. Rather, the positive modulators identified from plants act more like a dimmer switch, providing control over the intensity of activation according to the secreting level of endogenous GLP-1 and allowing the body to retain its physiological control over initiating receptor activation.
- novel GLP-1 receptor modulators e.g., activators
- compounds having Formula (I) or Formula (II) as described herein, or pharmaceutically acceptable salts thereof and uses thereof in regulating blood glucose levels and treating diabetes such as type I or type II diabetes.
- the GLP-1 receptor modulators described herein activates GLP-1 receptor only in the presence of GLP-1, which is different from the GLP-1 independent GLP-1 receptor activators known in the art. See, e.g., U.S. Pat. No. 8,501,982.
- the compounds described herein can be prepared by methods well known in the art.
- the compounds can be isolated from a native source, such as a plant.
- the compounds are chemically synthesized following routine synthetic routes, e.g., by Scheme 1 and Scheme 2 shown below.
- the chemicals used in the above-described synthetic routes may include, for example, solvents, reagents, catalysts, and protecting group and deprotecting group reagents.
- the methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compounds described herein.
- various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
- Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations , VCH Publishers (1989); T. W. Greene and P. G. M.
- a compound thus obtained can be further purified by methods known in the art (e.g., flash column chromatography, high performance liquid chromatography, or crystallization).
- the bioactivity of any of the compounds described herein can be verified via in vitro or in vivo assay systems known in the art, e.g., those described in the Examples below.
- compositions comprising GLP-1 Receptor Modulators and Therapeutic Uses Thereof
- Any of the compounds described herein may be useful in regulating blood glucose levels or treating diabetes in a subject via, e.g., modulating the GLP-1 receptor signaling pathways.
- a pharmaceutical composition that includes one or more compound described herein and a pharmaceutically acceptable carrier.
- a pharmaceutical composition described herein includes a compound described herein in an amount sufficient to regulate blood glucose level in a subject.
- the carrier in the pharmaceutical composition must be “acceptable” in the sense that it is compatible with the active ingredient of the composition, and preferably, capable of stabilizing the active ingredient and not deleterious to the subject to be treated.
- solubilizing agents such as cyclodextrins, which form specific, more soluble complexes with the compounds described herein, or one or more solubilizing agents, can be utilized as pharmaceutical excipients for delivery of the compounds described herein.
- examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.
- an effective amount of a pharmaceutical composition as described herein can be administered to a subject in need of the treatment via a suitable route.
- an “effective amount” is that amount of the one or more GLP-1 receptor modulator that alone, or together with further doses, produces the desired response, e.g. reduce the blood glucose levels in the subject.
- the desired response is inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily, although more preferably, it involves halting the progression of the disease permanently. This can be monitored by routine methods or can be monitored according to routine medical practices.
- the desired response to treatment of the disease or condition also can be delaying the onset or even preventing the onset of the disease or condition.
- Effective amounts will depend, of course, on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size, gender and weight, the duration of the treatment, the nature of concurrent therapy (if any), the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art, however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.
- the subject to be treated by any of the methods described herein can be a human patient, e.g., a human patient having, at risk for, or suspected of having an elevated blood glucose level or any disease/condition associated therewith, such as Type I or Type II diabetes, gestational diabetes, obesity, excessive appetite, insufficient satiety, and a metabolic disorder.
- a human patient can be identified by routine medical practices.
- the subject can be a non-human mammal, e.g., dog, cat, cow, pig, horse, sheep, or goat.
- the GLP-1 receptor modulator activates GLP-1 receptor only in the presence of GLP-1.
- any of the moculators described herein can be co-administered with GLP-1 or a functional variant thereof.
- treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of diabetes.
- treatment may be administered after one or more signs or symptoms have developed or have been observed.
- treatment may be administered in the absence of signs or symptoms of diabetes.
- treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
- composition described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
- parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
- a sterile injectable composition e.g., a sterile injectable aqueous or oleaginous suspension
- a sterile injectable preparation can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as TWEEN 80) and suspending agents.
- the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- suitable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or di-glycerides).
- Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
- These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.
- Other commonly used surfactants such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.
- a pharmaceutical composition for oral administration can be any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
- carriers which are commonly used include lactose and corn starch.
- Lubricating agents, such as magnesium stearate, are also typically added.
- useful diluents include lactose and dried corn starch.
- a nasal aerosol or inhalation composition can be prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
- a pharmaceutical composition described herein can also be administered in the form of suppositories for rectal administration.
- kits comprising one or more compound or pharmaceutical compositions described herein.
- a kit can further comprise a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container) for placing the compounds/compositions.
- a kit described herein may include a second container comprising a pharmaceutically acceptable excipient for dilution or suspension of a compound or pharmaceutical composition described herein.
- the compound or pharmaceutical composition provided in the first container and the second container are combined to form one unit dosage form.
- kits described herein may include instructions for using the kit (e.g., for administering a compound or pharmaceutical composition contained therein to a subject).
- a kit described herein may also include information as required by a regulatory agency such as the FDA. In certain embodiments, the information included in the kit is prescribing information.
- a kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
- a compound or pharmaceutical composition described herein may be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies.
- the additional pharmaceutical agents may be therapeutically active agents or prophylactically active agents.
- RJ-013 and RJ-014 are white solids.
- Data for RJ-013 Mp 134-135° C.; IR (film): 3350, 2918, 2865, 2840, 1652, 1452, 1384, 1123, 1088, 1035, 999 cm ⁇ 1 ; 1 H NMR (400 MHz, CDCl 3 ) ⁇ 5.88-5.84 (m, 1H), 3.99 (s.
- reaction contents were quenched with sat. NH 4 Cl (aq) at 0° C. and allowed to warm to room temperature.
- the phases were separated, and the aqueous layer was extracted with DCM (3 ⁇ 30 mL).
- the organic extracts were combined, washed with sat. NaHCO 3(aq) (80 mL) and brine (80 mL), dried over Na 2 SO 4 , and concentrated in vacuo.
- NCS 53 mg, 0.40 mmol
- stirring was maintained and the reaction monitored by TLC.
- the reaction was quenched with sat. NH 4 Cl (4 mL), the organic layer was separated, and the aqueous layer was extracted with DCM (3 ⁇ 5 mL). The DCM extracts were washed with brine (15 mL), dried over Na 2 SO 4 , and concentrated in vacuo.
- NCS (27.5 mg, 0.21 mmol) was then added. Stirring was maintained and the reaction monitored by TLC. After 24 h, the reaction was quenched with sat. NH 4 Cl (4 mL), the organic layer was separated, and the aqueous layer was extracted with DCM (3 ⁇ 5 mL). The DCM extracts were washed with brine (15 mL), dried over Na 2 SO 4 , and concentrated in vacuo.
- the reaction mixture was made basic with 3N NaOH (aq) and the tert-butyl alcohol was removed in vacuo. The residue was dissolved in water and extracted twice with hexanes. The water layer was acidified with 3N HCl (aq) and extracted twice with ether. The organic layer was washed with water and brine, dried over Na 2 SO 4 , and concentrated in vacuo.
- reaction mixture was stirred at room temperature for overnight and then the mixture was filtered, washed with CH 2 Cl 2 (2 mL). The filtrate was successively washed with aq. HCl, sat. NaHCO 3 solution and then brine.
- reaction contents were quenched with sat. NH 4 Cl (aq) (2 mL) at 0° C. and allowed to warm to room temperature.
- the phases were separated, and the aqueous layer was extracted with ether (3 ⁇ 2 mL).
- the organic extracts were combined, washed with sat. NaHCO 3(aq) (10 mL) and brine (10 mL), dried over Na 2 SO 4 , and concentrated in vacuo.
- Receptor endocytosis following arrestin recruitment and cAMP production subsequent to G ⁇ s coupling are two major immediate downstream cellular pathways upon GLP-1 receptor activation. Arrestin recruitment will lead to proliferation and anti-apoptosis of pancreatic b-cells (30, 31), while production of cAMP will lead to insulin secretion (Doyle et al., Pharmacology & Therapeutics, 2007, 113, 546).
- the ⁇ -arrestin2-GFP biosensor technology 45 was employed in screening for a plant extract library to identify those that can potentiate GLP-1 to elicit receptor endocytosis. Upon agonist binding to GPCR, the cytoplasmic arrestin rapidly translocate to and bind to the activated GPCR.
- Arrestin also mediates receptor internalization by targeting the receptor to clathrin-coated pits (46) which is a convergent step of GPCR activation.
- ⁇ -arrestin2-GFP biosensor technology involved less steps of enzymatic cascade and yielded more information on the compound (45), thus was used in the initial screening of plant crude extracts and also used as an assay for purifying active compounds from plant crude extracts there would found to be active in eliciting receptor endocytosis. Following the activity of this assay, a Hedychium coronarium (HC) extract was identified to potentiate GLP-1 in arrestin mediated GLP-1 receptor endocytosis.
- HC Hedychium coronarium
- galanal B Abilities of synthetic galanal B and its analogs to modulate GLP-1 dependent cAMP production in RINm5F cells and to modulate GLP-1 dependent receptor endocytosis were compared. This analysis revealed that by modifying structure of galanal B, novel compounds can be generated that selectively potentiate or suppress GLP-1 in G ⁇ s coupling pathway. Since it is well documented that type II diabetes still retain their ability to secret GLP-1 (43,44), it is expected that compound positively modulates GLP-1 by increasing the potency of GLP-1 should be potential drug of choice in anti-diabetics.
- U2OS osteosarcoma cell line stably expressing a ⁇ -arrestin2:GFP fusion protein was obtained from Norak Biosciences (now Molecular Devices, part of MDS Inc., Mississauga, Ontario).
- GLP-1 receptor expression construct was used to transfect the U2OS cell stably expressing ⁇ -arrestin2:GFP fusion protein and to obtain cell line stably co-expressing GLP-1 receptor and ⁇ -arrestin2:GFP fusion protein.
- High-content imaging of receptor endocytosis in cells was conducted with 0.03 mg/ml of ethanol extract from 2500 edible plant to identify potentiating activity for the GLP-1 dependent GLP-1 receptor endocytosis.
- Extracts were supplied at a concentration of 100 mg/ml in 100% DMSO.
- Three replicate 384-well assay microplates were plated with U2OS cells stably expressing GFP- ⁇ -arrestin2 fusion protein and the GLP-1 receptor at a density of 3,000 cells per well.
- Aliquots of 2.5 ⁇ L of 10 ⁇ stocks of plant extract in phenol red free MEM containing 1, 0.3, or 0.1 mg/ml of plant extract plus 40 nM of GLP-1 were transferred to each well of the cell assay plate, which contained 22.5 ⁇ L of phenol red free MEM.
- the 3 cell assay plates were incubated at room temperature for 60 min before fixation with 2% formaldehyde and labeling of the cell nuclei with 5 ⁇ g/mL of the DNA-binding dye Hoechst 33342 (Molecular Probes, Eugene, Oreg.) for 1 hr. Plates were washed with PBS twice and sealed and could be stored at 4° C. The final concentration of the extract in the cell plate was 0.1, 0.03 and 0.001 mg/ml, and the final DMSO concentration was 1%.
- BRET assays were performed to examine the effect of candidate GLP-1 receptor modulators on the intracellular cAMP levels in RINm5F cells (an insulin-secreting cell line), following routine technology. See, e.g., Bertrand et al., J. Recept Signal Transduct Res., 2002, 22(1-4):533-541; Barak et al., Mol. Pharmacol., 74(3):585-594 (2008); U.S. Pat. No. 8,647,887, and WO1999066324.
- the Spot Detector BIOAPPLICATION used the Hoechst-labeled nuclei to identify individual cells and then automatically counted and analyzed the GFP-labeled spots associate with each cell. In addition to the number of spots and the sum of their areas and pixel intensities, the BIOAPPLICATION also reports properties of the individual nuclei such as their area. The extent of receptor endocytosis response was expressed as % of that elicited by 1 ⁇ M of GLP-1.
- One unit of activity is defined as the activity that will reach 50% of maximal response in a well of 384-well plate.
- an ethanol extract library consisting 2500 edible plants was screened using ⁇ -arrestin2-GFP biosensor technology which is based on the observation that the ⁇ -arrestin2 binding of an activated receptor is a convergent step of GPCR signaling (45, 46).
- GLP1 (7-37) activates GLP 1 receptor dependent ⁇ -arrestin2 translocation in a dose dependent and saturable manner, and the EC 50 was measured to be 10 nM of GLP-1.
- This analysis demonstrated that 4 nM of GLP1 (7-37) is able to activate GLP-1 receptor to the level of 10 to 20% of the maximal response by 1 ⁇ M of the peptide.
- 0.1 mg/ml of plant ethanol extract was used to test its ability to enhance the agonistic effect of 4 nM of GLP-1 (7-37) on cells co-expressing GLP-1 receptor and ⁇ -arrestin2-GFP.
- 2500 herb ethanol extracts were screened for ability to enhance the GLP-1 receptor endocytosis elicited by 4 nM of GLP-1. 25 out of 2500 herb extracts were found to enhance the agonistic activity of 4 nM GLP-1 (7-37) from 20% to more than 80% of the maximal response, however, 9 out these 25 primary hits were false positive as judged by visualizing the corresponding images. The remaining 16 positive hits were tested for their selectivity to potentiate GLP-1 receptor by assaying their effect on PTHR, GIPR and BRS3 signaling. These selectivity tests revealed that 11 out these 16 positive hits will also activate PTHR or GIPR or BRS3, thus the remaining 5 plant extracts were found specifically potentiate GLP-1 receptor signaling.
- HC hypoglycemic effect or anti-diabetic effect on rodent or on other mammalian species
- HC is the only plant has not been reported for its effect on blood glucose excursion.
- HC ethanol extract was further subjected to characterizing its effects on the potency and efficacy of GLP-1 signaling. As shown in FIG.
- GFP-arrestin is evenly distributed in the cytosol of cells stably co-expresses ⁇ -arrestin1-GFP and GLP-1 receptor when the receptor is at resting stage, addition of 0.06 mg/ml of HC extract alone do not change the distribution of ⁇ -arrestin1-GFP, stimulation by 4 nM of GLP-1 leads to low level formation of vesicles contains (3-arrestin1-GFP and GLP-1 receptor in the cytosol and perinuclear region, much more vesicles of the receptor/ ⁇ -arrestin1-GFP complex was observed if cell co-incubated with 4 nM GLP-1 and 0.06 mg/ml of HC extract.
- 2B reveals titration of GLP-1 on GLP-1 receptor activation responses as % of that stimulated by 1 ⁇ M of GLP-1, showing that activation increased as GLP-1 increased from 1.5 nM and reached saturation at 324 nM of GLP-1, revealing that GLP-1 elicits GLP-1 receptor endocytosis in a dose dependent and saturable manner. While in the presence of 0.06 mg/ml ethanol extract of HC, the receptor activation started with 0.44 nM of GLP-1 and reached saturation at a GLP-1 concentration of 10 nM.
- FIG. 2C revealed the dose-response analysis of the titration of HC extract on receptor activation by 4 nM GLP-1; 4 nM of GLP-1 alone led to 20% of receptor activation while as the concentration of HC ethanol extract increased to 0.022 mg/ml the receptor activation increased, and when HC increased to 0.2 mg/ml the activation by 4 nM of GLP-1 was potentiated from 20% to 70%.
- Galanal B, Compound 1, and Compound 2 were synthesized as described above. Their effects on GLP-1 induced receptor endocytosis were investigated. As shown in FIG. 7 , dose response curve of GLP-1 and receptor endocytosis was left shifted by the presence of 0.003 mg/ml of these compounds. The EC 50 values and efficacy of galanal B, compound 1, and compound 2 are shown in Table 2 below. These results show that the potentiating effect of these compounds on GLP-1 dependent receptor endocytosis is highly dependent on the presence of GLP-1 since reduced levels of GLP-1 resulted in a decrease of the activity. The potentiating effects of these compounds are all blocked by GLP-1 receptor antagonist—exendin 9 ( FIG. 8 ), indicating their effects are mediated via GLP-1 receptor.
- GLP-1 receptor is coupled to G ⁇ s and leads to generation of cAMP in pancreatic ⁇ cells, to examine if the receptor endocytosis potentiating activities of the present compounds will translate into the ability to potentiate cAMP production, the effect of these compounds on the GLP-1 induced intracellular cAMP generation in RINm5F cell was tested via a BRET assay, using a cAMP biosensor as known in the art, which monitored the bioluminescence energy transferring as intracellular cAMP level increased (53).
- the affinity of compound 2 to enhance GLP-1 was determined to be 0.001 mg/ml. Similar dose of galanal B did not facilitate GLP-1 to stimulate cAMP production ( FIG. 9A ), galanal B did not significantly affect the dose-response curve of GLP-1 and cAMP production by 3 nM of GLP-1 was not changed by galanal B up to 0.04 mg/ml ( FIG. 9B ). By contrast, compound 1 remarkably suppresses GLP-1 elicited cAMP production in RINm5F cells and the dose response curve of GLP-1 on cAMP production was right shifted by almost 2 orders of magnitude, the EC 50 was increased from 7.8 to 360 nM ( FIG. 9A ).
- the affinity of compound 1 on GLP-1 elicited cAMP production was obtained by analyzing the dependence of compound 1 concentration on the cAMP production elicited by 60 nM of GLP-1. As revealed in FIG. 9C , 60 nM of GLP-1 generated cAMP more than 80% of that of saturation dose, as the concentration of compound 1 increased, the cAMP production reduced and reached bottom saturation at 0.003 mg/ml of compound 1. The affinity of compound 1 for GLP-1 in this assay was measured to be 0.0003 mg/ml.
- the effect of galanal B, compound 1 and compound 2 on the affinity of GLP-1 to elicit cAMP production in RINm5F cells are summarized in Table 3.
- GLP-1 receptor mediated signaling is a major target for treatment of type 2 diabetes, further its role in Alzheimer's disease and psoriasis is under clinical investigation.
- GLP-1 therapeutics are GLP-1 analogs or compounds with agonistic activity which may cause serious adverse effect upon chronic use.
- HC plant was identified that displays positive modulating action on GLP-1 elicited receptor endocytosis which requires the presence of GLP-1, indicating the identified activity functions as a GLP-1 potentiator with little intrinsic agonistic activity.
- galanal b After activity directed fractionation and purification, the structure of one of the active compounds was found to be galanal b.
- the purified galanal b displayed potent activity to potentiate GLP-1 to elicit recruiting ⁇ -arrestin2 to GLP-1 receptor and the following receptor endocytosis.
- This activity of galanal b is specific for GLP-1 as it did not show similar effect on PTH and its cognate receptor. The effect is highly dependent on the presence of GLP-1 and is abolished by the presence of GLP-1 receptor antagonist exendin 9.
- galanal B and its modified analogs were synthesized, followed by characterizing their ability (galanal b, compound 1, and compound 2) with respect to potentiating GLP-1 in eliciting receptor endocytosis and in stimulating cAMP production.
- the present findings raise question as how galanal b and its analogs share similar structure but stabilize quite distinct conformation of GLP-1 receptor which coupled comparably to ⁇ -arrestin-2 but display opposite coupling efficiency to the pathway of cAMP production.
- the first explanation is that the compound may bind to and modify the structure of GLP-1 receptor such that manifest as a pathway-dependent change in the signaling capacity upon binding to its orthosteric ligand GLP-1.
- the allosteric inhibitor of parturition (PDC 113.824) induces biased signaling when an orthosteric ligand is co-bound to the prostaglandin F2 ⁇ receptor (56).
- these compounds bind to GLP-1 to form a complex with distinct conformation which will stabilize a distinct set of receptor conformation upon binding and leads to positively or negatively modulate coupling efficiency to G ⁇ s pathway while display similarly the coupling efficiency to ⁇ -arrestin2 mediated receptor endocytosis.
- Subtle conformation changes in peptide agonists can lead to selective coupling of the receptor to its downstream signaling pathway.
- PTH1R parathyroid hormone receptor
- angiotensin II type 1A receptor ligands 57
- subtle structure change of the peptide ligands can profoundly stabilize a distinct conformation of the receptor protein that selectively affects the coupling efficiency of a particular downstream signaling pathway.
- GLP-1 glucagon-like peptide-1
- Compound 2 which potentiate GLP-1 dependent cAMP production by 1000 fold in RINm5F cells is a “true” positive modulator for GLP-1 because it lacks intrinsic agonistic activity as it does not elicit cAMP production in the absence of GLP-1.
- GLP-1 positive modulator function as a dimmer switch that amplifies the signaling depends on the plasma level of endogenous GLP-1, the intensity of activation of GLP-1 receptor is controlled by the physiologic concentration of GLP-1 secreted from intestine, thus will not stimulate target tissues constitutively. Since GLP-1 secretion in type 2 diabetes is comparable to or slightly defective as compare to healthy subject (43,44), GLP-1 positive modulator will be a potential compound to treat type 2 diabetes in the future.
- Positive modulator without intrinsic agonistic activity but only function to potentiate the activity of endogenous GLP-1 is expected to overcome the undesired effects by skipping the step of constitutive stimulation of the target tissues (58) associated with the chronic administration of GLP-1 analogs.
- GLP-1 receptors are also expressed in extra-pancreatic tissues, and trial data suggest GLP-1RAs also have effects beyond their glycaemic actions.
- GLP-1 signaling has been shown to be potential target for the treatment of immune dysfunction (Ahern et al., J Eur Acad Dermatol Venereol. 2013 November; 27(11):1440-3) (15), neurodegenerative diseases and cardiovascular disorders (Seufert et al., Diabetes Obes Metab. 2013 Dec. 24. doi: 10.1111/dom.12251; Egefjord et al., Dan Med J. 2012 October; 59(10):A4519). Biological effects triggered by GLP-1 receptor often result from the activation of multiple intracellular signaling pathways.
- the angiotensin II type 1A receptor the ⁇ -arrestin-biased ligand Sar1, D-Ala8 angiotensin II (TRV120027) has been shown to increase cardiac performance in anesthetized rats, whereas unbiased ligands reduce cardiac performance. There is also potential for improved PTH receptor agonists used for the treatment of osteoporosis.
- the ⁇ -arrestin-biased ligand (D-Trp12,Tyr34)-PTH(7-34) stimulates ⁇ -arrestin while blocking G-protein signaling and promotes anabolic bone formation in the absence of bone resorption.
- Screening signaling pathway selective compounds provides considerable scope for the identification of compounds that selectively target clinically useful GLP-1 signaling pathways and are more neutral or even block alternative pathways, which give rise to undesirable side effects. Given the risk of chronic usage of GLP-1 agonist in type 2 diabetes and potentially in other disorders, creating small molecules which modulates GLP-1 signaling pathway selectivity in a potent unique manner, may dramatically accelerate the rate at which critical pathway are selected.
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Abstract
Description
- The present application claims priority under 35 U.S.C. §119(e) to U.S. provisional patent applications, 61/827,674, filed May 27, 2013 and 61/839,870, filed Jun. 27, 2013, the entire content of each of which is incorporated by reference herein.
- Type II diabetes is characterized by decrease in peripheral tissue response to insulin in association with impaired cell function, which results in increase in fasting glycemia (1,2). Currently antihyperglycemic drugs such as metformin, sulfonylureas, or thiazolidinediones have been prescribed to promote insulin secretion or enhance insulin sensitivity, these drugs do not target all of the symptoms of type II DM (3,4). In cretin hormones (e.g., glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide GIP) are intestinally derived hormones that stimulate cAMP production via their cognate receptors in pancreatic b cells and subsequently leads to glucose dependent insulin secretion in response to food intake, play an important role in glucose homeostasis (5). Apart from its insulinotropic effects, GLP-1 also preserves pancreatic cells, suppresses glucagon release, reduces hepatic gluconeogenesis, it delays gastric emptying, reduces food intake by promoting satiety and reveals a favorable cardiometabolic profile (6-9). GLP-1 also displays extra-pancreatic effects, notably targeting the brain, immune system and heart, where it plays a role in neuroprotection (10-13), regulating immune responses (14-16) and cardioprotection (17-19). All these physiological actions of GLP-1 are mediated via interaction with its cognate G-protein coupled receptor—GLP-1 receptor on the target tissues. However, the exact downstream signaling of these extra-pancreatic physiological actions of GLP-1 still needed further investigation.
- GPCR (G protein-coupled receptor) signaling machinery was once considered as operating in an one-dimensional way, now has been proved to signal through several distinct mechanisms including those mediated by G proteins and by G-protein independent multifunctional adaptor proteins β-arrestins. In addition to heterotrimeric G proteins, two protein families specifically interact with the majority of GPCRs in their activated conformation: G protein-coupled receptor kinases (GRKs) and β-arrestins (20). GRKs and β-arrestins are considered to be G protein-independent signal transducers (20-22). In particular, (3-arrestins act as multifunctional scaffolds that interact with many protein partners (23) and protein kinases, thereby leading to the phosphorylation of numerous intracellular targets (24). Distinct selective coupling pathway will elicit quite distinct physiologic outcome and this finding has currently impacted further on the development of assay technology and search for pathway selective GPCR drug (25-28). Indeed, multi-pathway screening of against u-opioid receptor (29) and agonist for parathyroid hormone receptor (25) lead to discovery of compounds that provide therapeutic effect without the adverse side effects normally associated with these receptors, support the notion that pathway selective (biased) agonists may identify new classes of therapeutic agents that have fewer side effects. Though the insulinotropic effect of GLP-1 is mediated by stimulating cAMP generation in pancreatic cells via coupling to Gαs, other effects of GLP-1 have been shown to be mediated via coupling to β-arrestin. GLP-1 anti-apoptotic effect on pancreatic β-cells has been shown to be mediated by phosphorylating the pro-apoptotic protein Bad through β-arrestin1 dependent ERK1/2 activation (30). β-Arrestin1-mediated recruitment of c-Src is involved in proliferative action of GLP-1 on pancreatic β-cells (31). It will be interesting to know other extrapancreatic function of GLP-1 will be also mediated by arrestin coupling and it will be more straightforward to use pathway selective compounds to correlate cellular responses to specific signaling pathway. However, pathway selective compound is rarely available for GLP-1 receptor signaling.
- Current GLP-1 analogue therapeutics requires frequent subcutaneous administrations, and leads to reduced compliance and high prices in developing area. Typically, the plasma level of active GLP-1 is around 5 to 10 pM in the basal state, quickly rises to 20 to 50 pM after oral glucose or meal and will slowly declines to basal level over 2 hours (32-34). However, GLP-1 analogue therapeutics usually require to maintain constantly a supra-physiological level of GLP-1 analogues, thus lead to activating GLP-1 receptors constitutively and may cause severe complications upon chronic treatment (35-42).
- Identification of novel compounds that modulate the endogenous GLP-1 receptor signaling pathways can lead to the development of new therapeutics useful in regulating blood glucose levels, thereby treating diabetes or disorders associated with the GLP-1 receptor.
- This present disclosure is based on the discovery of novel GLP-1 receptor modulators (e.g., compounds of Formula (I) or (II), as being capable of modulating the endogenous glucagon-like peptide-1 (GLP-1) receptor signaling pathways and thus, may be useful in regulating blood glucose levels and/or treating diabetes and other disorders associated with the GLP-1 receptor. Accordingly, the present disclosure features GLP-1 receptor modulators such as compounds of Formula (I) or (II), or pharmaceutically acceptable salts thereof, and methods of using such compounds for regulating blood glucose levels and/or treating diabetes.
- In one aspect, the GLP-1 receptor modulators described herein are compounds of Formula (I):
- and pharmaceutically acceptable salts thereof, wherein:
- GA is hydrogen, ═O, ═S, —OR″, —SR″, —N(R″)2, alkenyl, alkynyl, an amide group, an ester group, a phosphate group, an aldehyde group, a nitrile group, an imino group, a ketone group, a thione group, an isonitrile group, an isothiocyanide group, a carbamate group, a thiocarbamate group, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms, wherein each instance of R″ is independently hydrogen, a cyclic or acyclic, saturated or unsaturated, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 16 carbon atoms;
- RA1, RA2, RA3, RA4, RA5, RA6, RA7, RA8, RA9, and RA10 are each independently hydrogen, halogen, —OR″, —N(R″)2, a carboxyl group, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbons, or RA1 and RA2 are joined to form ═O, or RA3 and RA4 are joined to form alkenyl;
- RA11, RA13, RA15, and RA17 are each independently hydrogen, halogen, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms;
- RA12, RA14, and RA16 are each independently halogen, —N(R″)2, —SR″, —OR″, alkyl, alkenyl, alkynyl, an amide group, a carboxyl group, an ester group, an aldehyde group, a nitrile group, an imino group, a ketone group, a thione group, an isonitrile group, an isothiocyanide group, a urea group, a carbamate group, or a thiocarbamate group, or RA14 and RA15 are joined to form ═O or ═S;
- RA20 is hydrogen, halogen, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms; and
- RA21 is hydrogen, halogen, —N(R″)2, —SR″, —OR″, —CH2OR″, alkenyl, alkynyl, an amide group, a carboxyl group, an ester group, an aldehyde group, a nitrile group, an imino group, a ketone group, a thione group, an isonitrile group, an isothiocyanide group, a carbamate group, a thiocarbamate group, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms.
- All compounds described herein include the compounds themselves, as well as their salts and stereoisomers, if applicable. The salts, for example, can be formed between a positively charged substituent (e.g., amino) on a compound and an anion. Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a negatively charged substituent (e.g., carboxylate) on a compound can form a salt with a cation. Suitable cations include, but are not limited to, sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as teteramethylammonium ion.
- In certain embodiments, a salt described herein is a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g., a human or non-human animal) without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. In certain embodiments, a pharmaceutically acceptable salt can be a salt described herein.
- Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972). The present disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
-
- Unless otherwise specified, a moiety described herein may be unsubstituted or may be substituted (e.g., at least one hydrogen atom of the moiety being replaced with a non-hydrogen atom or group). When a group described herein is substituted, the group may be substituted, as valency permits, with one or more substituents independently selected from the group consisting of C1-6 alkyl (e.g., unsubstituted C1-6 alkyl (e.g., methyl, ethyl, propyl, or butyl) or substituted C1-6 alkyl (e.g., —CF3, —CH2—CF3, or —C2F5)), —ORa1 (e.g., —OH, —OMe, or —OEt), —N(Ra1)2 (e.g., —NH2, —NHMe, or —NMe2), —SRa1 (e.g., —SH or —SMe), ═O, ═S, —CHO, —C(═O)N(Ra1)2 (e.g., —C(═O)NH2, —C(═O)NHMe, or —C(═O)NMe2), —CN, —C(═O)ORa1 (e.g., —C(═O)OH, —C(═O)OMe, or —C(═O)OEt), —OC(═O)Rb1 (e.g., —OC(═O)Me, —OC(═O)Et, or —OC(═O)(CH2)7CH═CHCH2CH═CH(CH2)4CH3), —OC(═O)ORa1 (e.g., —OC(═O)OMe, —OC(═O)OEt, or —OC(═O)O(CH2)7CH═CHCH2CH═CH(CH2)4CH3)), —C(Rb1)2ORa1 (e.g., —CH2—OH or —CH2—OMe), —C(Rb1)2SRa1 (e.g., —CH2—SH or —CH2—SMe), —C(Rb1)2N(Ra1)2 (e.g., —CH2—NH2, —CH2—NHMe, or —CH2—NMe2), and —C(Rb1)2C(═O)ORa1 (e.g., —CH2—OC(═O)OMe, —CH2—OC(═O)OEt, or —CH2—OC(═O)O(CH2)7CH═CHCH2CH═CH(CH2)4CH3)), wherein each instance of Ra1 is independently H, C1-6 alkyl (e.g., unsubstituted C1-6 alkyl (e.g., methyl, ethyl, propyl, or butyl) or substituted C1-6 alkyl (e.g., —CF3, —CH2—CF3, or —C2F5)), C2-6 alkenyl (e.g., unsubstituted C2-6 alkenyl (e.g., vinyl)), 3- to 10-membered cycloalkyl (e.g., unsubstituted 3- to 10-membered cycloalkyl (e.g., cyclopropyl)), or 6- to 10-membered aryl (e.g., phenyl (e.g., unsubstituted phenyl or substituted phenyl)), and each instance of Rb1 is independently H, halogen (e.g., F, Cl, Br, or I (iodine)), C1-6 alkyl (e.g., unsubstituted C1-6 alkyl (e.g., methyl, ethyl, propyl, or butyl) or substituted C1-6 alkyl (e.g., —CF3, —CH2—CF3, or —C2F5)), C2-6 alkenyl (e.g., unsubstituted C2-6 alkenyl (e.g., vinyl)), 3- to 10-membered cycloalkyl (e.g., unsubstituted 3- to 10-membered cycloalkyl (e.g., cyclopropyl)), or 6- to 10-membered aryl (e.g., phenyl (e.g., unsubstituted phenyl or substituted phenyl)).
- When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “C1-6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
- The term “(hetero)aliphatic” refers to aliphatic or heteroaliphatic. The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. The term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
- The term “alkyl” refers to a radical of a straight-chained (“unbranched”) or branched, saturated, hydrocarbon group. In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6).
- The term “alkenyl” refers to a radical of a straight-chained or branched hydrocarbon group having one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-6 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), and hexenyl (C6).
- The term “alkynyl” refers to a radical of a straight-chained or branched hydrocarbon group having one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-6 alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), and hexynyl (C6).
- “Heteroalkyl” refers to an alkyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-16 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-3 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted or substituted with one or more substituents.
- “Heteroalkenyl” refers to an alkenyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In some embodiments, a heteroalkenyl group has 2 to 16 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-16 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-3 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted or substituted with one or more substituents.
- “Heteroalkynyl” refers to an alkynyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In some embodiments, a heteroalkynyl group has 2 to 16 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-16 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-3 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted or substituted with one or more substituents.
- “Carbocyclyl,” “carbocycle,” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C1-10), cyclodecenyl (C1-10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C1-10), spiro[4.5]decanyl (C1-10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged. or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”). Carbocyclyl can be saturated, and saturated carbocyclyl is referred to as “cycloalkyl.” In some embodiments, carbocyclyl is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-4 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-4 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-4 cycloalkyl groups include the aforementioned C54cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-4 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3-10 cycloalkyl. Carbocyclyl can be partially unsaturated. Carbocyclyl including one or more C═C double bond in the carbocyclic ring is referred to as “cycloalkenyl.” Carbocyclyl including one or more C≡C triple bond in the carbocyclic ring is referred to as “cycloalkynyl.” Carbocyclyl includes aryl. “Carbocyclyl” also includes ring systems wherein the carbocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclic ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-10 carbocyclyl. In certain embodiments, the carbocyclyl group is substituted C3-10 carbocyclyl.
- “Heterocyclyl,” “heterocycle,” or “heterocyclic” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system, such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated (“heterocycloalkyl”) or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heterocyclyl includes heteroaryl. Heterocyclyl also includes ring systems wherein the heterocyclic ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclic ring, or ring systems wherein the heterocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclic ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.
- In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
- Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
- “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6-14 aryl. In certain embodiments, the aryl group is substituted C6-14 aryl.
- “Aralkyl” is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group. In certain embodiments, the aralkyl is optionally substituted benzyl. In certain embodiments, the aralkyl is benzyl. In certain embodiments, the aralkyl is optionally substituted phenethyl. In certain embodiments, the aralkyl is phenethyl.
- “Aralkenyl” is a subset of alkenyl and aryl, as defined herein, and refers to an optionally substituted alkenyl group substituted by an optionally substituted aryl group. An example of aralkenyl is styrenyl (i.e., —CH═CHPh).
- “Aralkynyl” is a subset of alkynyl and aryl, as defined herein, and refers to an optionally substituted alkynyl group substituted by an optionally substituted aryl group.
- “Heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
- In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.
- Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
- The term “oxo” refers to the a moiety of the formula: ═O.
- The term “amide” or “amide group” refers to a moiety of the formula: —N(Rpp)C(═O)Rqq, wherein Rpp is a nitrogen atom substituent described herein, and Rqq is a carbon atom substituent described herein.
- The term “ester” or “ester group” refers to a moiety of the formula: —C(═O)ORrr or —OC(═O)Rrr, wherein Rrr is an oxygen atom substituent described herein.
- The term “phosphate” or “phosphate group” refers to a moiety of the formula: —OP(═O)(ORoo)2, wherein each instance of Roo is independently an oxygen atom substituent described herein or a cationic counterion.
- The term “carboxyl” or “carboxyl group” refers to a moiety of the formula: —C(═O)OH.
- The term “aldehyde” or “aldehyde group” refers to a moiety of the formula: —C(═O)H.
- The term “thialdehyde” or “thialdehyde group” refers to a moiety of the formula: —C(═S)H.
- The term “nitrile” or “nitrile group” refers to a moiety of the formula: —CN or -L-CN, wherein L is substituted or unsubstituted, branched or unbranched, C1-16 alkylene; substituted or unsubstituted, branched or unbranched, C2-16 alkenylene; or substituted or unsubstituted, branched or unbranched, C2-16 alkynylene.
- The term “alcohol,” “alcohol group,” “hydroxyl,” or “hydroxy” refers to the group —OH. The term “substituted hydroxyl” or “substituted hydroxyl” refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from —ORaa, —ON(Rbb)2, —OC(═O)SRaa, —OC(═O)Raa, —OCO2Raa, —OC(═O)N(Rbb)2, —OC(═NRbb)Raa, —OC(═NRbb)ORaa, —OC(═NRbb)N(Rbb)2, —OS(═O)Raa, —OSO2Raa, —OSi(Raa)3, —OP(Rcc)2, —OP(Rcc)3, —OP(═O)2Raa, —OP(═O)(Raa)2, —OP(═O)(ORcc)2, —OP(═O)2N(Rbb)2, and —OP(═O)(NRbb)2, wherein Raa, Rbb, and Rcc are as defined herein.
- The term “amino” or “amino group” refers to a moiety of the formula: —N(Rii)2, wherein each instance of Rii is independently a nitrogen atom substituent described herein, or two instances of Rii are connected to form substituted or unsubstituted heterocyclyl. In certain embodiments, the amino is unsubstituted amino (i.e., —NH2). In certain embodiments, the amino is a substituted amino group, wherein at least one instance of Rii is not hydrogen.
- The term “imino” or “imino group” refers to a moiety of the formula: ═NRss, wherein Rss is a nitrogen atom substituent described herein.
- The term “ketone” or “ketone group” refers to a moiety of the formula: —C(═O)Rtt, wherein Rtt is a carbon atom substituent described herein.
- The term “thione” or “thione group” refers to a moiety of the formula: —C(═S)Ruu, wherein Ruu is a carbon atom substituent described herein.
- The term “isonitrile” or “isonitrile group” refers to a moiety of the formula: —NC.
- The term “isothiocyanide” or “isothiocyanide group” refers to a moiety of the formula: —SNC.
- The term “thioate” or “thioate group” refers to a moiety of the formula: —C(═O)SRzz or —C(═S)ORjj, wherein Rzz is a sulfur atom substituent described herein, and R is an oxygen atom substituent described herein.
- The term “thioamide” or “thioamide group” refers to a moiety of the formula: —N(Rmm)C(═S)Rnn, wherein Rmm is a nitrogen atom substituent described herein, and Rnn is a carbon atom substituent described herein.
- The term “dithioate” or “dithioate group” refers to a moiety of the formula: —C(═S)SRkk, wherein Rkk is a sulfur atom substituent described herein.
- The term “isocyanato” or “isocyanato group” refers to a moiety of the formula: —NCO.
- The term “isothiocyanato” or “isothiocyanato group” refers to a moiety of the formula: —NCS.
- The term “carbamate” or “carbamate group” refers to a moiety of the formula: —N(Rvv)C(═O)ORww or —OC(═O)N(Rvv)2, wherein each instance of Rvv is independently a nitrogen atom substituent described herein, and Rww is an oxygen atom substituent described herein.
- The term “urea” or “urea group” refers to a moiety of the formula: —N(Rzl)C(═O)N(Rzl)2, wherein each instance of Rzl is independently a nitrogen atom substituent described herein.
- The term “thiocarbamate” or “thiocarbamate group” refers to a moiety of the formula: —N(Rvv)C(═S)ORww or —OC(═S)N(Rvv)2, —N(Rvv)C(═O)SRyy or —SC(═O)N(Rvv)2, wherein each instance of Rvv is independently a nitrogen atom substituent described herein, Rww is an oxygen atom substituent described herein, and Ryy is a sulfur atom substituent described herein.
- “Halo” or “halogen” refers to fluorine (fluoro, F), chlorine (chloro or Cl), bromine (bromo or Br), or iodine (iodo or I).
- An atom, moiety, or group described herein may be unsubstituted or substituted, as valency permits, unless otherwise expressly provided. The term “substituted” refers to that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. In certain embodiments, the substituent is a carbon atom substituent. In certain embodiments, the substituent is a nitrogen atom substituent. In certain embodiments, the substituent is an oxygen atom substituent. In certain embodiments, the substituent is a sulfur atom substituent. In certain embodiments, a substituent may contribute to optical isomerism and/or stereo isomerism of a compound.
- Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO2, —N3, —SO2H, —SO3H, —OH, —ORaa, —ON(Rbb)2, —N(Rbb)2, —N(Rbb)3 +X−, —N(ORcc)Rbb, —SH, —SRaa, —SSRcc, —C(═O)Raa, —CO2H, —CHO, —C(ORcc)2, —CO2Raa, —OC(═O)Raa, —OCO2Raa, —C(═O)N(Rbb)2, —OC(═O)N(Rbb)2, —NRbbC(═O)Raa, —NRbbCO2Raa, —NRbbC(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —OC(═NRbb)Raa, —OC(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —OC(═NRbb)N(Rbb)2, —NRbbC(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa, —NRbbSO2R—, —SO2N(Rbb)2, —SO2Raa, —SO200Raa, —OSO2Raa, —S(═O)Raa, —OS(═O)Raa, —Si(Raa)3, —OSi(Raa)3—C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, —SC(═S)SRaa, —SC(═O)SRaa, —OC(═O)SRaa, —SC(═O)ORaa, —SC(═O)Raa, —P(═O)2Raa, —OP(═O)2Raa, —P(═O)(Raa)2, —OP(═O)(Raa)2, —OP(═O)(ORcc)2, —P(═O)2N(Rbb)2, —OP(═O)2N(Rbb)2, —P(═O)(NRbb)2, —OP(═O)(NRbb)2, —NRbbP(═O)(ORcc)2, —NRbbP(═O)(NRbb)2, —P(Rcc)2, —P(Rcc)3, —OP(Rcc)2, —OP(Rcc)3, —B(Raa)2, —B(ORcc)2, —BRaa(ORcc), C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; or two geminal hydrogens on a carbon atom are replaced with the group ═O, ═S, ═NN(Rbb)2, ═NNRbbC(═O)Raa, ═NNRbbC(═O)ORaa, ═NNRbbS(═O)2Raa, ═NRbb, or ═NORcc,
- each instance of Raa is, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
- each instance of Rbb is, independently, selected from hydrogen, —OH, —ORaa, —N(Rcc)2, —CN, —C(═O)Raa, —C(═O)N(Rcc)2, —CO2Raa, —SO2Raa, —C(═NRcc)ORaa, —C(═NRcc)N(Rcc)2, —SO2N(Rcc)2, —SO2Rcc, —SO2ORcc, —SORaa, —C(═S)N(Rcc)2, —C(═O)SRcc, —C(═S)SRcc, —P(═O)2Raa, —P(═O)(Raa)2, —P(═O)2N(Rcc)2, —P(═O)(NRcc)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rbb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
- each instance of Rcc is, independently, selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rdd is, independently, selected from halogen, —CN, —NO2, —N3, —SO2H, —SO3H, —OH, —ORee, —ON(Rff)2, —N(Rff)2, —N(Rff)3×, —N(ORee)Rff, —SH, —SRee, —SSRee, —C(═O)Ree, —CO2H, —CO2Ree, —OC(═O)Ree, —OCO2Ree, —C(═O)N(Rff)2, —OC(═O)N(Rff)2, —NRffC(═O)Ree, —NRffCO2Ree, —NRffC(═O)N(Rff)2, —C(═NRff)ORee, —OC(═NRff)Ree, —OC(═NRff)ORee, —C(═NRff)N(Rff)2, —OC(═NRff)N(Rff)2, —NRffC(═NRff)N(Rff)2, —NRffSO2Ree, —SO2N(Rff)2, —SO2Ree, —SO2ORee, —OSO2Ree, —S(═O)Ree, —Si(Ree)3, —OSi(Ree)3, —C(═S)N(Rff)2, —C(═O)SRee, —C(═S)SRee, —SC(═S)SRee, —P(═O)2Ree, —P(═O)(Ree)2, —OP(═O)(Ree)2, —OP(═O)(ORee)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two geminal Rdd substituents can be joined to form ═O or ═S;
- each instance of Ree is, independently, selected from C1-6 alkyl, C14 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups;
- each instance of Rff is, independently, selected from hydrogen, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, or two Rff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; and
- each instance of Rgg is, independently, halogen, —CN, —NO2, —N3, —SO2H, —SO3H, —OH, —OC1-6 alkyl, —ON(C1-6 alkyl)2, —N(C1-6 alkyl)2, —N(C1-6 alkyl)3 +X−, —NH(C1-6 alkyl)2 +X−, —NH2(C1-6 alkyl)+X−, —NH3 +X−, —N(OC1 alkyl)(C1-6 alkyl), —N(OH)(C1-6 alkyl), —NH(OH), —SH, —SC1-6 alkyl, —SS(C1-6 alkyl), —C(═O)(C1-6 alkyl), —CO2H, —CO2(C1-6 alkyl), —OC(═O)(C1-6 alkyl), —OCO2(C1-6 alkyl), —C(═O)NH2, —C(═O)N(C1-6 alkyl)2, —OC(═O)NH(C1-6 alkyl), —NHC(═O)(C1-6 alkyl), —N(C1-6 alkyl)C(═O)(C1-6 alkyl), —NHCO2(C1-6 alkyl), —NHC(═O)N(C1-6 alkyl)2, —NHC(═O)NH(C1-6 alkyl), —NHC(═O)NH2, —C(═NH)O(C1-6 alkyl), —OC(═NH)(C1-6 alkyl), —OC(═NH)OC1-6 alkyl, —C(═NH)N(C1-6 alkyl)2, —C(═NH)NH(C1-6 alkyl), —C(═NH)NH2, —OC(═NH)N(C1-6 alkyl)2, —OC(NH)NH(C1-6 alkyl), —OC(NH)NH2, —NHC(NH)N(C1-6 alkyl)2, —NHC(═NH)NH2, —NHSO2(C1-6 alkyl), —SO2N(C1-6 alkyl)2, —SO2NH(C1-6 alkyl), —SO2NH2, —SO2C1-6 alkyl, —SO2OC1-6 alkyl, —OSO2C1-6 alkyl, —SOC1-6 alkyl, —Si(C1-6 alkyl)3, —OSi(C1-6 alkyl)3-C(═S)N(C1-6 alkyl)2, C(═S)NH(C1-6 alkyl), C(═S)NH2, —C(═O)S(C1-6 alkyl), —C(═S)SC1-6 alkyl, —SC(═S)SC1-6 alkyl, —P(═O)2(C1-6 alkyl), —P(═O)(C1-6 alkyl)2, —OP(═O)(C1-6 alkyl)2, —OP(═O)(OC1-6 alkyl)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rgg substituents can be joined to form ═O or ═S; wherein X− is a counterion.
- A “counterion” or “anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F−, Cl−, Br−, I−), NO3 −, ClO4 −, OH−, H2PO4 −, HSO4 −, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, and glycolate).
- Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, —OH, —ORaa, —N(Rcc)2, —CN, —C(═O)Raa, —C(═O)N(Rcc)2, —CO2Raa, —SO2Raa, —C(═NRbb)Raa, —C(═NRcc)ORaa, —C(═NRcc)N(Rcc)2, —SO2N(Rcc)2, —SO2Rcc, —SO2ORcc, —SORaa, —C(═S)N(Rcc)2, —C(═O)SRcc, —C(═S)SRcc, —P(═O)2Raa, —P(═O)(Raa)2, —P(═O)2N(Rcc)2, —P(═O)(NRcc)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Raa, Rbb, Rcc, and Rdd are as defined herein.
- In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups include, but are not limited to, —OH, —ORaa, —N(Rcc)2, —C(═O)Raa, —C(═O)N(Rcc)2, —CO2Raa, —SO2Raa, —C(═NRcc)Raa, —C(═NRcc)ORaa, —C(═NRcc)N(Rcc)2, —SO2N(Rcc)2, —SO2Rcc, —SO2ORcc, —SORaa, —C(═S)N(Rcc)2, —C(═O)SRcc, —C(═S)SRcc, C1-10 alkyl (e.g., aralkyl, heteroaralkyl), C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
- For example, nitrogen protecting groups include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.
- Nitrogen protecting groups also include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.
- Nitrogen protecting groups further include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.
- Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacyl derivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).
- Exemplary oxygen atom substituents include, but are not limited to, —Raa, —C(═O)SRaa, —C(═O)Raa, —CO2Raa, —C(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —S(═O)Raa, —SO2Raa, —Si(Raa)3, —P(Rcc)2, —P(Rcc)3, —P(═O)2Raa, —P(═O)(Raa)2, —P(═O)(ORcc)2, —P(═O)2N(Rbb)2, and —P(═O)(NRbb)2, wherein Raa, Rbb, and Rcc are as defined herein. In certain embodiments, the oxygen atom substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, methyl, t-butyloxycarbonyl (BOC or Boc), methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).
- Exemplary sulfur atom substituents include, but are not limited to, —Raa, —C(═O)SRaa, —C(═O)Raa, —CO2Raa, —C(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —S(═O)Raa, —SO2Raa, —Si(Raa)3, —P(Rcc)2, —P(Rcc)3, —P(═O)2Raa, —P(═O)(Raa)2, —P(═O)(ORcc)2, —P(═O)2N(Rbb)2, and —P(═O)(NRbb)2, wherein Raa, Rbb, and Rcc are as defined herein. In certain embodiments, the sulfur atom substituent present on a sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
- In certain embodiments, GA can be hydrogen, ═O, ═S, —OR″, —SR″, —NR″H, alkenyl, alkynyl, an amide group, an ester group, an aldehyde group, a nitrile group, an imino group, a ketone group, a thione group, an isonitrile group, an isothiocyanide group, a carbamate group, a thiocarbamate group, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms, wherein each instance of R″ can be independently hydrogen, a cyclic or acyclic, saturated or unsaturated, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 16 carbon atoms;
- RA1, RA2, RA3, RA4, RA5, RA6, RA7, RA8, RA9, and RA10 can each independently be hydrogen, halogen, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbons;
- RA11, RA12, RA13, RA15, RA16, and RA17 can each independently be hydrogen, halogen, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms;
- RA14 can be halogen, —NR″H, —SR″, —OR″, alkenyl, alkynyl, an amide group, an ester group, an aldehyde group, a nitrile group, an imino group, a ketone group, a thione group, an isonitrile group, an isothiocyanide group, a carbamate group, or a thiocarbamate group;
- RA20 can be hydrogen, halogen, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms; and
- RA21 can be hydrogen, halogen, —NR″H, —SR″, —OR″, alkenyl, alkynyl, an amide group, an ester group, an aldehyde group, a nitrile group, an imino group, a ketone group, a thione group, an isonitrile group, an isothiocyanide group, a carbamate group, a thiocarbamate group, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms.
- In certain embodiments, a compound of Formula (I) can be of Formula (I-A):
- In certain embodiments, a compound of Formula (I) can be of the formula:
- In certain embodiments, a compound of Formula (I) can be of Formula (I-B):
- In certain embodiments, a compound of Formula (I) can be of Formula (I-C):
- In certain embodiments, a compound of Formula (I) can be of Formula (I-D):
- In certain embodiments, GA can be hydrogen. In certain embodiments, GA can be ═O, ═S, —SR″, —OR″, —N(R″)2, —OH, —SH, or —NH2. In certain embodiments, GA can be can be ═O. In certain embodiments, GA can be —OR″ (e.g., —OH, —O(substituted or unsubstituted C1-6 alkyl), or —OC(═O)(substituted or unsubstituted C1-6 alkyl)). In certain embodiments, GA can be can be ═S. In certain embodiments, GA can be —SR″ (e.g., —SH). In certain embodiments, GA can be —N(R″)2, —NHR″ (such as —NH(substituted or unsubstituted C1-6 alkyl) or —NHC(═O)(substituted or unsubstituted C1-6 alkyl)), or —NH2. In certain embodiments, GA can be can be alkenyl (e.g., acyclic, substituted or unsubstituted, C1-6 alkenyl, such as ═CHC(═O)O(substituted or unsubstituted C1-6 alkyl)). In certain embodiments, GA can be can be a phosphate group (e.g., —OP(═O)(acyclic, substituted or unsubstituted, C1-6 alkyl)2). In certain embodiments, RA1 can be hydrogen. In certain embodiments, RA1 can be halogen. In certain embodiments, RA1 can be an acyclic, substituted or unsubstituted, branched or unbranched, aliphatic group having 1 to 6 carbons (e.g., acyclic, substituted or unsubstituted, branched or unbranched, C1-6 alkyl (such as —CF3)). In certain embodiments, RA1 can be —OR″ (e.g., —OH). In certain embodiments, RA1 can be —N(R″)2 (e.g., —NMe2). In certain embodiments, RA2 can be hydrogen. In certain embodiments, RA1 and RA2 can be joined to form ═O. In certain embodiments, RA3 can be hydrogen. In certain embodiments, RA3 can be acyclic, substituted or unsubstituted, branched or unbranched, C1-6 alkyl (e.g., methyl, —CF3, —CH2Br, —CH2OH, —CH2OC(═O)(substituted or unsubstituted C1-6 alkyl), or ethyl). In certain embodiments, RA3 can be carboxyl. In certain embodiments, RA4 can be hydrogen. In certain embodiments, RA4 can be acyclic, substituted or unsubstituted, branched or unbranched, C1-6 alkyl (e.g., methyl, —CF3, —CH2C(═O)(substituted or unsubstituted C1-6 alkyl), or ethyl). In certain embodiments, RA3 and RA4 can be joined to form alkenyl (e.g., ═CH2). In certain embodiments, RA5 can be hydrogen. In certain embodiments, RA5 can be acyclic, substituted or unsubstituted, branched or unbranched, C1-6 alkyl (e.g., methyl or —CH2OCF3). In certain embodiments, RA5 cannot be hydrogen. In certain embodiments, RA6 can be acyclic, substituted or unsubstituted, branched or unbranched, C1-6 alkyl (e.g., methyl, ethyl, —CH2OH, —CH2C(═O)Me, or —CH2C(═S)Me). In certain embodiments, RA6 cannot be —CH3. In certain embodiments, RA7 can be hydrogen. In certain embodiments, RA7 can be acyclic, substituted or unsubstituted, branched or unbranched, C1-6 alkyl (e.g., methyl). In certain embodiments, RA7 can be —OR″ (e.g., —OH). In certain embodiments, RA8 can be hydrogen. In certain embodiments, RA8 can be acyclic, substituted or unsubstituted, branched or unbranched, C1-6 alkyl (e.g., methyl). In certain embodiments, at least one of RA7 and RA8 cannot be hydrogen. In certain embodiments, RA9 can be hydrogen. In certain embodiments, RA9 can be acyclic, substituted or unsubstituted, branched or unbranched, C1-6 alkyl (e.g., methyl). In certain embodiments, RA10 can be hydrogen. In certain embodiments, at least one of RA9 and RA10 cannot be hydrogen. In certain embodiments, RA11 can be hydrogen. In certain embodiments, RA12 can be hydrogen. In certain embodiments, RA12 can be an amino group (e.g., —N(R″)2, —NHR″, or —NH2). In certain embodiments, RA13 is absent. In certain embodiments, at least one of RA12 and RA13 cannot be hydrogen. In certain embodiments, RA14 can be halogen, —NR″H, —SR″, —OR″, alkenyl, alkynyl, an amide group, a carboxyl group, an ester group, an aldehyde group, a nitrile group, an imino group, a ketone group, a thione group, an isonitrile group, an isothiocyanide group, a carbamate group, or a thiocarbamate group. In certain embodiments, RA14 can be hydrogen. In certain embodiments, RA14 can be alkyl (e.g., acyclic, substituted or unsubstituted, branched or unbranched, C1-6 alkyl (e.g., —CH2CF3, —CH2OR″ (such as —CH2OH), —CH2SR″ (such as —CH2SH), —CH2N(R″)2 (such as —CH2NHMe or —CH2NH2), —CH2C(═O)(acyclic, substituted or unsubstituted, branched or unbranched, C1-20 aliphatic (such as
- or —CH2C(═O)N(R″)2 (such as —CH2C(═O)NH(substituted or unsubstituted C1-6 alkyl))). In certain embodiments, RA14 cannot be —CH2OH. In certain embodiments, RA14 can be a carboxyl group. In certain embodiments, RA14 can be an ester group (e.g., —C(═O)O(acyclic, substituted or unsubstituted, branched or unbranched, C1-6 alkyl), such as —C(═O)OMe). In certain embodiments, RA14 can be an aldehyde group. In certain embodiments, RA14 can be a ketone group (e.g., —C(═O)-(acyclic, substituted or unsubstituted, branched or unbranched, C1-6 alkyl), such as —C(═O)Me). In certain embodiments, RA14 can be a urea group (e.g., —NHC(═O)—NH(substituted or unsubstituted phenyl), such as —NHC(═O)—NHPh). In certain embodiments, RA15 can be absent. In certain embodiments, RA14 and RA15 can be joined to form ═O or ═S. In certain embodiments, RA16 can be hydrogen. In certain embodiments, RA16 can be a carbamate group (e.g., —NHC(═O)O(acyclic, substituted or unsubstituted, branched or unbranched, C1-6 alkyl), such as —NHC(═O)OEt). In certain embodiments, RA17 can be hydrogen. In certain embodiments, at least one of RA16 and RA17 cannot be hydrogen. In certain embodiments, RA20 can be hydrogen. In certain embodiments, RA20 can be absent. In certain embodiments, RA21 can be hydrogen. In certain embodiments, RA21 can be a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms. In certain embodiments, RA21 can be acyclic, substituted or unsubstituted, branched or unbranched, C1-6 alkyl (e.g., —CH2OR″ (such as —CH2OH, —CH2C(═O)OMe, or —CH2C(═O)(acyclic, substituted or unsubstituted, branched or unbranched, C1-20 aliphatic (such as
- —CH2SR″ (such as —CH2SH); —CH2SC(═O)(substituted or unsubstituted phenyl); or —CH2N(R″)2 (such as —CH2NHR″ (e.g., —CH2NHMe) or —CH2NH2)). In certain embodiments, RA21 can be acyclic, substituted or unsubstituted, branched or unbranched, C2-6 alkenyl (e.g., —CH═CHCH3 or —CH═NBn). In certain embodiments, RA21 can be an aldehyde group. In certain embodiments, RA21 can be a carboxyl group. In certain embodiments, each instance of R″ can independently be hydrogen. In certain embodiments, each instance of R″ can independently be acyclic, substituted or unsubstituted, branched or unbranched, C1-6 alkyl (e.g., methyl, ethyl, propyl, or butyl).
- The tricyclic ring system
- of Formula (I) may include substituents in addition to one or more of RA1 to RA17, RA20 to RA21, and GA, as valency permits. In certain embodiments, the tricyclic ring system of Formula (I) can further be substituted at one or two of the positions marked with “*”:
- In certain embodiments, the tricyclic ring system of Formula (I) can further be substituted with one or more substituents independently selected from the group consisting of halogen; substituted and unsubstituted C1-6 aliphatic (e.g., unsubstituted C1-6 alkyl, such as —CH3); and —OR″ (e.g., —OH).
- In certain embodiments, at least one of RA1, RA2, RA5, RA7, RA8, RA9, RA10, RA11, RA12, RA13, RA15, RA16, and RA17 cannot be hydrogen. In certain embodiments, at least one of RA3, RA4, and RA6 cannot be —CH3. In certain embodiments, when RA21 is —CHO and GA is —OH or ═O, each of RA14 and RA15 cannot be —CHO.
- In certain embodiments, the compound of Formula (I) cannot be of the formula:
- wherein:
- GA is —OR″ or —N(R″)2;
- RA14 is an amide group, a nitrile group, an ester group, or substituted methyl; and
- RA21 is an aldehyde group, —CH2OR″, or an ester group.
- In another aspect, the GLP-1 receptor modulators described herein are compounds of Formula (II):
- and pharmaceutically acceptable salts thereof, wherein:
- G is hydrogen, ═O, ═S, —NR′H, —SR′, or —OR′, wherein R′ is hydrogen, an ester group, a ketone group, a thione group, or a cyclic or acyclic, saturated or unsaturated, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 16 carbon atoms;
- W is —O—, —S— or —NR′—;
- X and Y are each independently a single bond or a saturated or unsaturated, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 3 carbon atoms;
- R1, R2, R3, R4, R5, R6, R7, R8, R9, R12 and R13 are each independently hydrogen, halogen, or a cyclic or acyclic, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms, or R2 and R3 may join to form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- R10 and R11 are each independently hydrogen, halogen, an amino group, an amide group, an ester group, an aldehyde group, a nitrile, an imino group, a ketone group, a thione group, an isonitrile group, an isothiocyanide group, a carbamate group, a thiocarbamate group, or a cyclic or acyclic, saturated or unsaturated, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1 to 6 carbon atoms;
- R14 is hydrogen or a saturated or unsaturated, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1-16 carbon atoms;
- R15 is hydrogen or a saturated or unsaturated, substituted or unsubstituted, branched or unbranched, (hetero)aliphatic group having 1-6 carbon atoms; and
- R21 is
- or an aldehyde group.
- In certain embodiments, X and Y can each be methylene; R1 can be methyl; R2, R3 and the two carbon atoms directly bonded therewith can form a 3,3-dimethyl cyclohexane ring;
- R4, R5, R6, R7, R8, R9, R10, R12, and R13 can each be hydrogen; R11 can be an amide group, an acid group, an ester group, an aldehyde group, an alcohol group, a carbamate group, a thiocarbamate, a carbonate, a nitrile group, an amino group, or an imino group; and the bond between the two carbon atoms directly bonded with R10 and R11 can be a double bond.
- In certain embodiments, X and Y can each be methylene; R1 can be methyl; R2, R3 and the two carbon atoms directly bonded therewith can form a 3,3-dimethyl cyclohexane ring; R4, R5, R6, R7, R8, R9, R10, R12, and R13 can each be hydrogen; R11 can be an amide group, an acid group, an ester group, an aldehyde group, an alcohol group, a carbamate group, a thiocarbamate, a carbonate, a nitrile group, an amino group, or an imino group; W can be —O—; R12, R13, R14, and R15 can each be hydrogen; G can be ═O; and the bond between the two carbon atoms directly bonded with R10 and R11 can be a double bond.
- In certain embodiments, a compound of Formula (II) can be of Formula (II-A):
- In certain embodiments, a compound of Formula (II) can be of Formula (II-B):
- In certain embodiments, a compound of Formula (II) can be of Formula (II-C):
- In certain embodiments, a compound of Formula (II) can be of Formula (II-D):
- In certain embodiments, G can be can be ═O. In certain embodiments, G can be —OR′ (e.g., —OH, —O(substituted or unsubstituted C1-6 alkyl), or —OC(═O)(substituted or unsubstituted C1-6 alkyl)). In certain embodiments, G can be can be ═S. In certain embodiments, G can be —SR′ (e.g., —SH or —S(substituted or unsubstituted C1-6 alkyl)). In certain embodiments, G can be —NHR′ (such as —NH(substituted or unsubstituted C1-6 alkyl) or —NHC(═O)(substituted or unsubstituted C1-6 alkyl)) or —NH2. In certain embodiments, W can be —O—. In certain embodiments, W can be —S—. In certain embodiments, W can be —NR′— (e.g., —N(substituted or unsubstituted C1-6 alkyl)- or —NH—). In certain embodiments, X can be methylene. In certain embodiments, X can be ethanediyl, vinylene bridge, or propanediyl. In certain embodiments, Y can be methylene. In certain embodiments, Y can be ethanediyl, vinylene bridge, or propanediyl. In certain embodiments, R1 can be substituted or unsubstituted, branched or unbranched, C1-6 alkyl (e.g., methyl, —CH2OH, —CH2C(═O)Me, or —CH2C(═S)Me). In certain embodiments, R1 cannot be —CH3. In certain embodiments, R2, R3, and the two carbon atoms directly bonded therewith form cycloalkyl (e.g., a 3,3-dimethyl cyclohexane ring
- that is unsubstituted or substituted (e.g., substituted with —OH)). In certain embodiments, R2, R3, and the two carbon atoms directly bonded therewith cannot form
- that is unsubstituted. In certain embodiments, R4, R5, R6, R7, R8, R9, R10, R12, and R13 can each be hydrogen. In certain embodiments, R4 can be hydrogen. In certain embodiments, R4 can be substituted or unsubstituted, branched or unbranched, C1-6 alkyl (e.g., methyl or —CH2OCF3). In certain embodiments, R4 cannot be hydrogen. In certain embodiments, R5 can be hydrogen. In certain embodiments, R5 can be substituted or unsubstituted, branched or unbranched, C1-6 alkyl (e.g., methyl). In certain embodiments, R5 can be —OR′ (e.g., —OH). In certain embodiments, R6 can be hydrogen. In certain embodiments, R6 can be substituted or unsubstituted, branched or unbranched, C1-6 alkyl (e.g., methyl). In certain embodiments, at least one of R5 and R6 cannot be hydrogen. In certain embodiments, R7 can be hydrogen. In certain embodiments, R7 can be substituted or unsubstituted, branched or unbranched, C1-6 alkyl (e.g., methyl). In certain embodiments, R8 can be hydrogen. In certain embodiments, at least one of R7 and R8 cannot be hydrogen. In certain embodiments, R9 can be hydrogen. In certain embodiments, R10 can be hydrogen. In certain embodiments, R10 can be an amino group (e.g., —N(R′)2, —NHR′, or —NH2). In certain embodiments, R11 can be hydrogen. In certain embodiments, R11 can be an amide group, an ester group, an aldehyde group, a carbamate group, a thiocarbamate, a nitrile group, an amino group, an imino group, or substituted or unsubstituted, branched or unbranched, C1-6 alkyl. In certain embodiments, R11 can be an ester group, an aldehyde group, a ketone group, or substituted or unsubstituted, branched or unbranched, C1-6 alkyl. In certain embodiments, R11 can be substituted or unsubstituted, branched or unbranched, C1-6 alkyl (e.g., —CH2CF3, —CH2OR′ (such as —CH2OH), —CH2SR′ (such as —CH2SH), —CH2N(R′)2 (such as —CH2NHMe or —CH2NH2), or —CH2C(═O)N(R′)2 (such as —CH2C(═O)NH(substituted or unsubstituted C1-6 alkyl))). In certain embodiments, R11 cannot be —CH2OH. In certain embodiments, R11 can be an ester group (e.g., —C(═O)O(substituted or unsubstituted, branched or unbranched, C1-6 alkyl), such as —C(═O)OMe). In certain embodiments, R11 can be an aldehyde group. In certain embodiments, R11 can be a ketone group (e.g., —C(═O)-(substituted or unsubstituted, branched or unbranched, C1-6 alkyl), such as —C(═O)Me). In certain embodiments, R12 can be hydrogen. In certain embodiments, R13 can be hydrogen. In certain embodiments, R14 can be hydrogen. In certain embodiments, R14 can be substituted or unsubstituted, branched or unbranched, C1-6 alkyl (e.g., —C(═O)OMe or —C(═O) (substituted or unsubstituted, C2-20 alkenyl). In certain embodiments, R21 can be
- In certain embodiments, R21 can be —CH2OH. In certain embodiments, R21 can be an aldehyde group. In certain embodiments, R15 can be hydrogen. In certain embodiments, R15 can be absent. In certain embodiments, the bond between the two carbon atoms directly bonded with R10 and R11 can be a double bond. In certain embodiments, the bond between the two carbon atoms directly bonded with R10 and R11 can be a single bond. In certain embodiments, R′ can be hydrogen. In certain embodiments, R′ can be substituted or unsubstituted, branched or unbranched, C1-6 alkyl (e.g., methyl, ethyl, propyl, or butyl).
- In certain embodiments, at least one of R4, R5, R6, R7, R8, R9, and R10 cannot be hydrogen. In certain embodiments, R1 cannot be —CH3. In certain embodiments, when R21 is —CHO and G is —OH or ═O, R11 cannot be —CHO.
- In certain embodiments, the compound of Formula (II) cannot be of the formula:
- wherein:
- G is —OR′ or —NR′H;
- R11 is an amide group, a nitrile, an ester group, or substituted methyl; and
- R21 is an aldehyde group or —CH2OR14.
- In certain embodiments, a compound described herein cannot be of the formula:
- In certain embodiments, a compound described herein cannot be of the formula:
- wherein Rx is a phosphorous-containing group.
- Exemplary compounds described herein include, but are not limited to:
- and pharmaceutically acceptable salts thereof, wherein
- In still another aspect, this present disclosure features pharmaceutical compositions including one or more of the GLP-1 receptor modulators described herein and a pharmaceutically acceptable carrier.
- In yet another aspect, this present disclosure features methods for regulating blood glucose level and/or treating diabetes in a subject. The method comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition described herein. In certain embodiments, the subject is a human (e.g., a human patient having, at risk for, or suspected of having diabetes, e.g., type I or type II diabetes.
- In still another aspect, this present disclosure features methods of treating diabetes in a subject, the method including administering to a subject in need thereof an effective amount (e.g., a therapeutically effective amount) of a pharmaceutical composition described herein.
- The methods described above can also include the step of identifying a subject in need of the treatment, e.g., a human patient having or at risk for developing abnormal blood glucose levels or any disorder associated therewith.
- In further another aspect, the present disclosure features kits comprising a pharmaceutical composition described herein and optionally, instructions for using the kits.
- Also within the scope of this present disclosure are a pharmaceutical composition as described herein for use in regulating blood glucose level and/or treating diabetes in a subject, and the use of such a pharmaceutical composition for the manufacture of a medicament for regulating blood glucose level and/or treating diabetes in a subject.
- Other features or advantages of the present disclosure will be apparent from the following detailed description of several embodiments, and also from the appending claims.
-
FIG. 1 is a chart showing the effect of GLP-1 (7-36) on endocytosis medicated by GLP-1 receptor. The GLP-1R/β-arrestin2 GFP double stable expression U2OS cells were plated in 384-well plastic plates at a density of 3000 cell/well and cultured overnight. Wells were treated with vehicle or various concentrations of GLP-1(7-36) for 60 min at room temperature in the presence (◯) or absence (□) of 1 μM ofexendin 9. -
FIG. 2 shows the activity of an ethanol extract of Hedychium coronarium (HC) in potentiating the GLP-1 activity. (Panel A) Cell images of GLP-1 receptor endocytosis elicited by 0 or 4 nM of GLP-1 in the presence or absence of 0.06 mg/ml ethanol extract of HC. (Panel B) Dose response data of GLP-1 from 0.15 nM to 324 nM on GLP-1 receptor activation in the presence (▾) or absence (▪) of 0.0 6 mg/ml of ethanol extract of HC. (Panel C) Dose response data of ethanol extract of HC from 0.0025 mg/ml to 0.2 mg/ml on GLP-1 receptor activation by 4 nM of GLP-1. -
FIG. 3 includes charts showing normal phase silica gel chromatograms of HC ethyl acetate partition fraction. 7 g of EtOAc partition material was subjected to normal phase silica gel chromatography and resolved into 37 fractions. The activity was assayed for each fraction (the ability of 0.002 mg/ml partially purified compounds to potentiate the receptor endocytosis elicited by 4 nM of GLP-1) and expressed as % of the maximal activity elicited by 1 μM of GLP-1. ♦ represents weight of each fraction. ▪ indicates the activity of each fraction. I is the pooledfraction 5 to fraction 12. -
FIG. 4 shows an exemplary fractionation of I (the pooledfraction 5 to fraction 12) on a KROMASIL C18 column. 1.7 gram of I was injected into a KROMASIL C18 column (250×50 mm, 10 μm) eluted at flow rate of 109 ml/min with a gradient started with 57% acetonitrile in water and finally with 100% acetonitrile. Weight of each fraction (♦) and (▪) indicates activity of each fraction. -
FIG. 5 shows exemplary results of a dose response analysis of galanal B on GLP-1 (Panel A) or PTH (Panel B) induced receptor endocytosis. The GLP-1R/3-arrestin2 GFP (Panel A) or PTHR/β-arrestin 2 GFP (Panel B) double stable expression U2OS cells were plated in 384-well plastic plates at a density of 3000 cell/well and cultured overnight. Dose titration of galanal B on cell stimulated with 4 nM of GLP-1 7-36 (FIG. 5A ) or stimulated with 15 nM of PTH (Panel B). Panel C shows exemplary results of a dose response data of GLP-1 from 0.15 nM to 324 nM on GLP-1 receptor activation in the presence (▾) or absence (▪) of 0.001 mg/ml of galanal B. -
FIG. 6 shows that galanal B potentiated GLP-1 elicited GLP-1 receptor endocytosis. Dose response data of GLP-1 from 0.15 nM to 324 nM on GLP-1 receptor activation in the presence (▾) of 0.001 mg/ml of galanal B (Panel A) or in the absence (▪) of 0.001 mg/ml of galanal B (Panel B). -
FIG. 7 shows that galanal B,compound 1, andcompound 2 increased the potency of GLP-1 dependent receptor endocytosis. Dose response titration of GLP-1 from 0.15 nM to 324 nM on GLP-1 receptor endocytosis in the presence (◯), (∇), (□) of 0.0001 mg/ml of galanal B, 0.001 mg/ml ofcompound 1, 0.001 mg/ml ofcompound 2, respectively, or GLP-1 alone (▴). -
FIG. 8 shows thatexendin 9 diminished positivemodulation effect compound 1,compound 2, and galanal B on GLP-1 elicited GLP-1 receptor endocytosis. (Panel A) Titration of GLP-1 on GLP-1 receptor endocytosis in the presence of 0.0001 mg/ml of galanal B (), absence of galanal B (▴), and in the presence of 0.0001 mg/ml of galanal B plus 1.8 mM of Exendin 9 (▪). (Panel B) Titration of GLP-1 on GLP-1 receptor endocytosis in the presence of 0.001 mg/ml of compound 2 (), absence of compound 2 (▴) and in the presence of 0.001 mg/ml ofcompound 2 plus 1.8 mM of Exendin 9 (▪). (Panel C) Titration of GLP-1 on GLP-1 receptor endocytosis in the presence of 0.001 mg/ml of compound 1 (), absence of compound 1 (▴) and in the presence of 0.001 mg/ml ofcompound 1 and 1.8 mM of Exendin 9 (▪). -
FIG. 9 shows thatcompound 1 suppressed, andcompound 2 potentiated, GLP-1 dependent cAMP production in RINm5F cells (Panel A) Dose response titration of GLP-1 in the presence of 0.003 mg/ml of galanal B (◯), compound 2 (⋄), compound 1 (∇), or GLP-1 alone (). (Panel B) Dose response of galanal (◯) or compound 2 (Δ) on cAMP production in RINm5F cells stimulated by 3 nM of GLP-1. (Panel C) Dose response of compound 1 () on cAMP production in RINm5F cells elicited by 60 nM of GLP-1. -
FIG. 10 shows that potentiation effect ofcompound 2 on GLP-1 elicited cAMP generation is blocked byexendin 9 and MDL 12330A. (Panel A) Titration ofexendin 9 on cAMP production in RINm5F cells stimulated by 2 nM of GLP-1 in the presence (Δ) and absence () of 0.0025 mg/ml ofcompound 2. (Panel B) Titration of GLP-1 on cAMP production in RIMm5F cells (◯) or in the presence of 0.0025 mg/ml of compound 2 (a) or in the presence of 0.0025 mg/ml ofcompound 2 plus 250 mM of MDL 12330A (b). -
FIG. 11 shows the effect ofcompound 1 andcompound 2 on cAMP production in RINm5F cells elicited by GIP and Glucagon. (Panel A) Titration of GIP on the production of cAMP from RINm5F cells (Δ) or in the presence of 0.025 mg/ml of compound 2 (□) or compound 1 (◯). (Panel B) Titration of glucagon on the production of cAMP from RINm5F cells (▴) or in the presence of 0.025 mg/ml of compound 2 (▪) or compound 1 (). - In an attempt to identify orally active and physiologically more compliant GLP-1 therapeutics for diabetes (e.g., type II diabetes) and compounds that selectively regulates the GLP-1 pathway, edible plants were screened for activities that modulate the GLP-1 receptor signaling. In particular, plant extracts were screened to identify components that positively modulate GLP-1 receptor signaling in a GLP-1 dependent manner. The compounds identified in the screening process do not act merely in an on-and-off manner, as those GLP-1 therapies known in the art. Rather, the positive modulators identified from plants act more like a dimmer switch, providing control over the intensity of activation according to the secreting level of endogenous GLP-1 and allowing the body to retain its physiological control over initiating receptor activation.
- Accordingly, described herein are novel GLP-1 receptor modulators (e.g., activators) such as compounds having Formula (I) or Formula (II) as described herein, or pharmaceutically acceptable salts thereof, and uses thereof in regulating blood glucose levels and treating diabetes such as type I or type II diabetes. The GLP-1 receptor modulators described herein activates GLP-1 receptor only in the presence of GLP-1, which is different from the GLP-1 independent GLP-1 receptor activators known in the art. See, e.g., U.S. Pat. No. 8,501,982.
- Preparation of GLP-1 Receptor Modulators
- The compounds described herein can be prepared by methods well known in the art. In some examples, the compounds can be isolated from a native source, such as a plant. In other examples, the compounds are chemically synthesized following routine synthetic routes, e.g., by
Scheme 1 andScheme 2 shown below. - The chemicals used in the above-described synthetic routes may include, for example, solvents, reagents, catalysts, and protecting group and deprotecting group reagents. The methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compounds described herein. In addition, various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.
- A compound thus obtained can be further purified by methods known in the art (e.g., flash column chromatography, high performance liquid chromatography, or crystallization). The bioactivity of any of the compounds described herein can be verified via in vitro or in vivo assay systems known in the art, e.g., those described in the Examples below.
- Pharmaceutical Compositions Comprising GLP-1 Receptor Modulators and Therapeutic Uses Thereof
- Any of the compounds described herein may be useful in regulating blood glucose levels or treating diabetes in a subject via, e.g., modulating the GLP-1 receptor signaling pathways.
- A pharmaceutical composition that includes one or more compound described herein and a pharmaceutically acceptable carrier. In certain embodiments, a pharmaceutical composition described herein includes a compound described herein in an amount sufficient to regulate blood glucose level in a subject. The carrier in the pharmaceutical composition must be “acceptable” in the sense that it is compatible with the active ingredient of the composition, and preferably, capable of stabilizing the active ingredient and not deleterious to the subject to be treated. For example, solubilizing agents such as cyclodextrins, which form specific, more soluble complexes with the compounds described herein, or one or more solubilizing agents, can be utilized as pharmaceutical excipients for delivery of the compounds described herein. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and
D&C Yellow # 10. - To practice the methods described herein, an effective amount of a pharmaceutical composition as described herein can be administered to a subject in need of the treatment via a suitable route.
- An “effective amount” is that amount of the one or more GLP-1 receptor modulator that alone, or together with further doses, produces the desired response, e.g. reduce the blood glucose levels in the subject. In the case of treating a particular disease or condition such as Type I or Type II diabetes, characterized by dysregulated GLP-1 receptor signaling, the desired response is inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily, although more preferably, it involves halting the progression of the disease permanently. This can be monitored by routine methods or can be monitored according to routine medical practices. The desired response to treatment of the disease or condition also can be delaying the onset or even preventing the onset of the disease or condition.
- Effective amounts will depend, of course, on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size, gender and weight, the duration of the treatment, the nature of concurrent therapy (if any), the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art, however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.
- The subject to be treated by any of the methods described herein can be a human patient, e.g., a human patient having, at risk for, or suspected of having an elevated blood glucose level or any disease/condition associated therewith, such as Type I or Type II diabetes, gestational diabetes, obesity, excessive appetite, insufficient satiety, and a metabolic disorder. Such a human patient can be identified by routine medical practices. Alternatively, the subject can be a non-human mammal, e.g., dog, cat, cow, pig, horse, sheep, or goat.
- The GLP-1 receptor modulator activates GLP-1 receptor only in the presence of GLP-1. Thus, when a subject's endogenous level of GLP-1 is too low, any of the moculators described herein can be co-administered with GLP-1 or a functional variant thereof.
- The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of diabetes. In some embodiments, treatment may be administered after one or more signs or symptoms have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of diabetes. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
- The pharmaceutical composition described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
- A sterile injectable composition, e.g., a sterile injectable aqueous or oleaginous suspension, can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as TWEEN 80) and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or di-glycerides). Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents. Other commonly used surfactants such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.
- A pharmaceutical composition for oral administration can be any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added. A nasal aerosol or inhalation composition can be prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. A pharmaceutical composition described herein can also be administered in the form of suppositories for rectal administration.
- Also within the scope of the present disclosure are kits (e.g., pharmaceutical packs) comprising one or more compound or pharmaceutical compositions described herein. Such a kit can further comprise a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container) for placing the compounds/compositions. In some embodiments, a kit described herein may include a second container comprising a pharmaceutically acceptable excipient for dilution or suspension of a compound or pharmaceutical composition described herein. In some embodiments, the compound or pharmaceutical composition provided in the first container and the second container are combined to form one unit dosage form.
- A kit described herein may include instructions for using the kit (e.g., for administering a compound or pharmaceutical composition contained therein to a subject). A kit described herein may also include information as required by a regulatory agency such as the FDA. In certain embodiments, the information included in the kit is prescribing information. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
- A compound or pharmaceutical composition described herein may be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. The additional pharmaceutical agents may be therapeutically active agents or prophylactically active agents.
- Without intent to limit the scope of the present disclosure, exemplary compounds and methods of using or making such, as well as their related results according to the embodiments of the present disclosure are given below. Note that titles or subtitles may be used in the examples for convenience of a reader, which in no way should limit the scope of the present disclosure. Moreover, certain theories are proposed and disclosed herein; however, in no way they, should limit the scope of the present disclosure so long as the present disclosure is practiced according to the present disclosure without regard for any particular theory or scheme of action.
-
- A solution of (±)-(4aS,6aR,11aS,11bR)-9-(hydroxymethyl)-4,4,11b-trimethyl tetradecahydro-1H-cyclohepta[a]naphthalen-7-ol, TEMPO, and TBACl in DCM and aqueous solution of NaHCO3 (0.5M) and K2CO3 (0.05M) were vigorously stirred at room temperature. NCS was then added. Stirring was maintained and the reaction monitored by TLC. The reaction was quenched with sat. NH4Cl, the organic layer was separated, and the aqueous layer was extracted with DCM (three times). The DCM extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was coated on silica gel and purified by flash column chromatography to give (±)-(4aS,6aR,11aS,11bR)-7-hydroxy-4,4,11b-trimethyltetradecahydro-1H-cyclohepta[a]naphthalene-9-carbaldehyde (RJ-002) as a white solid.
-
- A solution of (±)-(6aS,11aS,11bR)-
methy oxo methyl -
- To a solution of (±)-(6aS,11aS,11bR)-
methyl methy -
- To a solution of (±)-(6aS,1aS,11bR)-
methyl -
- To a solution of (±)-(4aS,4bR,10aS)-4b,8,8-trimethyldodecahydro-phenanthren-1(4bH)-one (890 mg, 3.59 mmol) in THF (18 mL) was added LHMDS (1.0 M in THF, 5.4 mL, 5.38 mmol) at −78° C. The mixture was allowed to warm slowly to 0° C. over the course of 2 h. Then, cooled down to −78° C., and NCCOOMe (0.43 mL, 5.38 mmol) and TMEDA (0.73 mL, 5.38 mmol) were added dropwise to the reaction mixture. Let it slowly warmed to room temperature and the stirring was continued overnight. The reaction contents were quenched with 1N HCl(aq) (40 mL) and extracted with DCM (3×20 mL). The organic extracts were combined, washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo. To a solution of Et2Zn (1.0 M in hexane, 5.4 mL, 5.38 mmol) in DCM (30 mL) under ice-bath was added neat CH2I2. The mixture was stirred at 0° C. for 1 h, and then the aforementioned crude in DCM (30 mL) was added. After 5 minutes, removed the ice-bath, and the stirring was continued for 3 h at room temperature. The reaction contents were quenched with sat. NH4Cl(aq) at 0° C. and allowed to warm to room temperature. The phases were separated, and the aqueous layer was extracted with DCM (3×30 mL). The organic extracts were combined, washed with sat. NaHCO3(aq) (80 mL) and brine (80 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (gradient from 1:48→1:24 EtOAc:hexanes) to afford (±)-(6aS,11aS,11bR)-
methyl -
- To a solution of (±)-(6aS,7S,11aS,11bR)-9-(hydroxymethyl)-4,4,11b-trimethyl-2,3,4,4a,5,6,6a,7,8,11,11a,11b-dodecahydro-1H-cyclohepta[a]naphthalen-7-ol (RJ-014) (6.8 mg, 0.023 mmol) in DCM (0.27 mL) at room temperature was added Dess-Martin periodinane (29.3 mg, 0.069 mmol), and the stirring was continued for 6 h. The reaction was quenched by 1M Na2SO3(aq) (0.5 mL) and sat. NaHCO3(aq) (0.5 mL) and stirred for another 30 minutes. The phases were separated, and the aqueous layer was extracted with DCM (3×4 mL). The organic extracts were combined, washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (1:19 EtOAc:hexanes) to afford (±)-(6aS,11aS,11bR)-4,4,11b-trimethyl-7-oxo-2,3,4,4a,5,6,6a,7,8,11,11a,11b-dodecahydro-1H-cyclohepta[a]naphthalene-9-carbaldehyde (RJ-017) (4.4 mg, 65%). Data for RJ-017: Mp 87-88° C.; IR (film): 2927, 2867, 2837, 1707, 1686, 1639, 1461, 1444, 1388, 1366, 1251, 1152, 1139, 1114 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 6.85-6.82 (m, 1H), 3.45-3.35 (m, 2H), 2.72-2.62 (m, 1H), 2.56 (td, J=12.0 Hz, J=4.0 Hz, 1H), 2.24-2.13 (m, 1H), 1.88-1.79 (m, 2H), 1.79-1.72 (m, 1H), 1.71-1.66 (m, 1H), 1.66-1.58 (m, 1H), 1.54-1.30 (m, 4H), 1.18 (td, J=13.4 Hz, J=4.0 Hz, 1H), 1.00-0.90 (m, 2H), 0.88 (s, 6H), 0.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 210.6, 192.3, 153.8, 137.3, 54.7, 53.9, 51.0, 41.8, 38.6, 37.4, 36.4, 33.3, 33.3, 29.8, 28.6, 21.5, 21.0, 18.7, 14.2; HRMS (EI) calcd for C19H28O2 [M]+: 288.2089. found: 288.2084.
-
- A solution of (±)-(6aS,7S,11aS,11bR)-9-(hydroxymethyl)-4,4,11b-trimethyl-2,3,4,4a,5,6,6a,7,8,11,11a,11b-dodecahydro-1H-cyclohepta[a]naphthalen-7-ol (RJ-014) (58 mg, 0.20 mmol), TEMPO (3.1 mg, 0.02 mmol), and TBACl (5.5 mg, 0.02 mmol) in DCM (2 mL) and aqueous solution of NaHCO3 (0.5M, 1 mL) and K2CO3 (0.05M, 1 mL) were vigorously stirred at room temperature. NCS (53 mg, 0.40 mmol) was then added. Stirring was maintained and the reaction monitored by TLC. After 8 h, the reaction was quenched with sat. NH4Cl (4 mL), the organic layer was separated, and the aqueous layer was extracted with DCM (3×5 mL). The DCM extracts were washed with brine (15 mL), dried over Na2SO4, and concentrated in vacuo. The residue was coated on silica gel and purified by flash column chromatography (gradient from 1:19→1:4 EtOAc:hexanes) to give (±)-(7S,11bR)-7-hydroxy-4,4,11b-trimethyl-2,3,4,4a,5,6,6a,7,8,11,11a,11b-dodecahydro-1H-cyclohepta[a]naphthalene-9-carbaldehyde (RJ-018) (43 mg, 75%) as a white solid. Data for RJ-018: Mp 148-150° C.; IR (film) 3470, 2934, 2918, 2859, 2846, 1671, 1645, 1444, 1387, 1109, 1082, 1046, 737 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 6.96-6.92 (m, 1H), 3.82 (d, J=6.8 Hz, 1H), 2.97 (dd, J=15.2 Hz, J=8.0 Hz, 1H), 2.53 (dd, J=14.6 Hz, J=9.0 Hz, 1H), 2.30 (d, J=15.6 Hz, 1H), 2.11-2.00 (m, 1H), 1.90-1.59 (m, 6H), 1.59-1.49 (m, 1H), 1.49-1.34 (m, 3H), 1.34-1.21 (m, 1H), 1.18-1.07 (m, 2H), 0.90 (dd, J=12.9 Hz, J=3.5 Hz, 1H), 0.85 (s, 3H), 0.84 (s, 3H), 0.81 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 193.8, 156.3, 142.3, 69.8, 54.6, 47.2, 46.1, 41.8, 39.1, 37.7, 33.4, 33.4, 30.8, 29.2, 28.8, 21.8, 21.4, 18.8, 14.0; HRMS (ESI) calcd for C19H30O2 [M+Na]+: 313.2143. found: 313.2151.
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- A solution of (±)-(6aS,7R,11aS,11bR)-9-(hydroxymethyl)-4,4,11b-trimethyl-2,3,4,4a,5,6,6a,7,8,11,11a,11b-dodecahydro-1H-cyclohepta[a]naphthalen-7-ol (RJ-013) (30 mg, 0.10 mmol), TEMPO (1.6 mg, 0.01 mmol), and TBACl (2.8 mg, 0.01 mmol) in DCM (1 mL) and aqueous solution of NaHCO3 (0.5M, 0.5 mL) and K2CO3 (0.05M, 0.5 mL) were vigorously stirred at room temperature. NCS (27.5 mg, 0.21 mmol) was then added. Stirring was maintained and the reaction monitored by TLC. After 24 h, the reaction was quenched with sat. NH4Cl (4 mL), the organic layer was separated, and the aqueous layer was extracted with DCM (3×5 mL). The DCM extracts were washed with brine (15 mL), dried over Na2SO4, and concentrated in vacuo. The residue was coated on silica gel and purified by flash column chromatography (gradient from 1:9→1:4 EtOAc:hexanes) to give (±)-(7R,11bR)-7-hydroxy-4,4,11b-trimethyl-2,3,4,4a,5,6,6a,7,8,11,11a,11b-dodecahydro-1H-cyclohepta[a]naphthalene-9-carbaldehyde (RJ-019) (19 mg, 64%) as a white solid. Data for RJ-019: Mp 142-144° C.; IR (film): 3507, 2963, 2917, 2863, 2844, 1678, 1648, 1436, 1384, 1345, 1302, 1212, 1041, 1007 cm−1; 1H NMR (500 MHz, CDCl3) δ 9.38 (s, 1H), 6.96-6.93 (m, 1H), 3.49-3.43 (m, 1H), 2.70 (dd, J=16.0 Hz, J=8.5 Hz, 1H), 2.63-2.49 (m, 2H), 2.30-2.20 (m, 1H), 2.07-2.00 (m, 1H), 1.89-1.82 (m, 1H), 1.79-1.70 (m, 1H), 1.70-1.52 (m, 4H), 1.52-1.43 (m, 1H), 1.43-1.29 (m, 2H), 1.14 (td, J=13.5 Hz, J=3.0 Hz, 1H), 1.09-0.93 (m, 2H), 0.87 (s, 3H), 0.85 (s, 3H), 0.82 (s, 3H), 0.82-0.78 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 193.9, 157.6, 140.5, 74.4, 54.8, 53.1, 48.1, 42.0, 38.8, 38.0, 33.4, 33.4, 32.6, 28.8, 28.1, 21.7, 21.6, 18.9, 14.0; HRMS (ESI) calcd for C19H30O2 [M+Na]+: 313.2143. found: 313.2137.
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- A mixture of Cp2TiCl2 (794 mg, 2.20 equiv.) and Zinc powder (625 mg, 6.60 equiv) in deoxygenated THF (14 mL) was stirred at room temperature (30 min) until the red solution turned green. The green Ti(III) solution was slowly added via cannula to the stirred solution of (E)-methyl 2-(cyanomethyl)-4-((1R,2R,8aS)-5,5,8a-trimethyl octahydro-1H-spiro[naphthalene-2,2′-oxiran]-1-yl)but-2-enoate (500 mg, 1.45 mmol) in THF (15 mL) and stirred for 12 h. After this, an excess of saturated NaH2PO4 was added, and the mixture was stirred for 30 min. The mixture was filtered to remove insoluble titanium salts. The product was extracted into ether (3×30 mL), and the combined organic layers were washed with saturated NaHCO3 (20 mL) and brine, dried over Na2SO4, concentrated and the crude product was column chromatographied (EtOAc-hexanes, 1:9) to afford (6aR,1aR,11bS)-methyl6a-(hydroxymethyl)-4,4,11b-trimethyl-7-oxo-2,3,4,4a,5,6,6a,7,8,11,11a,11b-dodecahydro-1H-cyclohepta[a]naphthalene-9-carboxylate (RJ-022) as colorless needles (302 mg, 60%).
- Characteristic data of RJ-022: [α]25 D −21.1 (c 0.93, CHCl3); mp 179-180° C. 1H NMR (400 MHz, CDCl3) δ 7.07 (dt, J=6.2, 3.1 Hz, 1H), 4.14-3.98 (m, 2H), 3.93 (ddd, J=13.9, 6.7, 2.8 Hz, 1H), 3.74 (s, 3H), 3.49 (d, J=13.9 Hz, 1H), 2.80 (dd, J=8.0, 5.8 Hz, 1H), 2.65-2.44 (m, 2H), 2.18 (dd, J=11.8, 2.1 Hz, 1H), 2.02-1.95 (m, 1H), 1.81 (d, J=12.4 Hz, 1H), 1.66 (ddd, J=14.0, 8.7, 3.8 Hz, 2H), 1.53-1.34 (m, 5H), 1.18 (td, J=13.5, 4.1 Hz, 2H), 0.95 (s, 3H), 0.88 (s, 3H), 0.82 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 214.6, 167.0, 143.7, 124.3, 63.3, 56.8, 56.5, 52.2, 50.6, 41.6, 39.8, 37.9, 37.7, 33.4, 33.1, 32.4, 26.3, 21.3, 18.4, 18.1, 16.1. IR (film) 3542, 2935, 1708, 1702, 1640, 1440, 1386, 1263, 1165, 1115, 1060, 753 cm−1. HRMS (FAB+) calcd for C21H33O4 [(M+H)+] 349.2379. found 349.2380.
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- A solution of sodium chlorite (12 mg, 0.13 mmol) and NaH2PO4 (41 mg, 0.34 mmol) in H2O (0.2 mL) was added dropwise to a rapidly stirred solution of (±)-(7S,11bR)-7-hydroxy-4,4,11b-trimethyl-2,3,4,4a,5,6,6a,7,8,11,11a,11b-dodecahydro-1H-cyclohepta[a]naphthalene-9-carbaldehyde (RJ-018) (10 mg, 0.034 mmol) and 2-methyl-2-butene (36 μL, 0.34 mmol) in tert-butyl alcohol (0.34 mL) at room temperature and the stirring was continued for 30 h. The reaction mixture was made basic with 3N NaOH(aq) and the tert-butyl alcohol was removed in vacuo. The residue was dissolved in water and extracted twice with hexanes. The water layer was acidified with 3N HCl(aq) and extracted twice with ether. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was coated on silica gel and purified by flash column chromatography (1:9 EtOAc:MeOH) to give (7S,11aS,11bR)-7-hydroxy-4,4,11b-trimethyl-2,3,4,4a,5,6,6a, 7,8,11,111a,11b-dodecahydro-1H-cyclohepta[a]naphthalene-9-carboxylic acid (RJ-026) (7.8 mg, 74%) as a white solid. Data for RJ-026: Mp 229-231° C.; IR (film): 3448, 2938, 2865, 2837, 1701, 1458, 1440, 1385, 1363, 1121, 1104, 1039, 1016, 969 cm−1; 1H NMR (500 MHz, CD3OD) δ 7.16-7.13 (m, 1H), 3.83-3.80 (m, 1H), 2.93-2.85 (m, 1H), 2.48 (d, J=15.5 Hz, 1H), 2.37 (dd, J=15.0 Hz, J=9.0 Hz, 1H), 2.00-1.87 (m, 2H), 1.84-1.76 (m, 1H), 1.76-1.65 (m, 2H), 1.65-1.57 (m, 1H), 1.50-1.44 (m, 1H), 1.44-1.27 (m, 4H), 1.19 (td, J=13.5 Hz, J=4.0 Hz, 1H), 1.11 (t, J=10.8 Hz, 1H), 0.94-0.89 (m, 1H), 0.88 (s, 3H), 0.87 (s, 3H), 0.85 (s, 3H); 13C NMR (125 MHz, CD3OD) δ 171.7, 145.1, 133.3, 71.3, 56.3, 49.6, 47.0, 43.2, 40.2, 38.8, 34.4, 34.0, 33.2, 31.1, 28.7, 22.7, 22.3, 20.0, 14.5; HRMS (EI) calcd for C19H30O3 [M]+: 306.2195. found: 313.2196.
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- A solution of (6aR,11aR,11bS)-methyl 6a-(hydroxymethyl)-4,4,11b-trimethyl-7-oxo-2,3,4,4a,5,6,6a,7,8,11,11a,11b-dodecahydro-1H-cyclohepta[a]naphthalene-9-carboxylate (40 mg, 0.11 mmol) in DCM (1 mL) was treated with Dess Martin periodinane (70 mg, 0.16 mmol), which was added in portions at room temperature. After being stirred for 1 h, the mixture was diluted with saturated aqueous Na2S2O3 (1 mL) and NaHCO3 (1 mL) were added. The resulting mixture was stirred vigorously for 30 min and the layers were separated. The aqueous phase was extracted with CH2Cl2 and the combined organic extracts were washed with brine and concentrated under vacuum. The residue was column chromatographied (EtOAc-hexanes, 1:11) to obtain (6aR,11aR,11bS)-methyl6a-formyl-4,4,11b-trimethyl-7-oxo-2,3,4,4a,5,6,6a,7,8,11,11a,11b-dodecahydro-1H-cyclohepta[a]naphthalene-9-carboxylate (RJ-029) as white solid (80%).
- Characteristic data of RJ-029: mp 86-88° C. IR (film) 2948, 1727, 1693, 1645, 1437, 1389, 1366, 1258, 1115, 1064, 733 cm−1. 1H NMR (400 MHz, CDCl3) δ 9.84 (d, J=1.0 Hz, 1H), 7.16 (dt, J=6.3, 3.1 Hz, 1H), 3.92-3.80 (m, 1H), 3.75 (d, J=6.6 Hz, 3H), 3.54 (d, J=14.2 Hz, 1H), 2.89-2.65 (m, 2H), 2.40-2.26 (m, 2H), 1.84-1.70 (m, 2H), 1.68-1.58 (m, 1H), 1.53-1.39 (m, 4H), 1.18 (td, J=13.4, 4.3 Hz, 1H), 1.01-0.92 (m, 2H), 0.89 (s, 3H), 0.79 (s, 3H), 0.75 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 206.2, 199.6, 166.6, 142.6, 125.0, 66.5, 55.4, 52.4, 51.4, 41.6, 38.8, 38.2, 37.6, 33.3, 33.2, 31.2, 25.5, 21.3, 18.8, 18.5, 15.2. HRMS (ES−) calcd for C21H29O4 [(M−H)+] 345.2066. found 345.2059.
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- To the linoleic acid (LA) (10.4 mg, 0.037 mmol), DMAP (5.5 mg, 0.44 mmol) was added at room temperature, to this, ((6aR,7R,11aR,11bS)-7-hydroxy-4,4,11b-trimethyl-2,3,4,4a,5,6,6a,7,8,11,11a,11b-dodecahydro-1H-cyclohepta[a]naphthalene-6a,9-diyl)dimethanol (12 mg, 0.037 mmol) in CH2Cl2 (0.5 mL) was added, stirred and cooled to 0° C. and DCC (9 mg, 0.044 mmol) was directly added to the above mixture. The reaction mixture was stirred at room temperature for overnight and then the mixture was filtered, washed with CH2Cl2 (2 mL). The filtrate was successively washed with aq. HCl, sat. NaHCO3 solution and then brine. The CH2Cl2 layer was dried over Na2SO4, concentrated and the resulting residue was column chromatographied to give (9Z,12Z)-(7-hydroxy-6a-(hydroxymethyl)-4,4,11b-trimethyl-2,3,4,4a,5,6,6a,7,8,11,11a,11b-dodecahydro-1H-cyclohepta[a]naphthalene-9-yl)methyl octadeca-9,12,dienoate (RJ-033) as colorless oil (40%) and (9Z,9′Z,12Z,12′Z)-((6aR,7R,11bS)-(7-hydroxy-4,4,11b-trimethyl-2,3,4,4a,5,6,6a,7,8,11,11a,11b-dodecahydro-1H-cyclohepta[a]naphthalene-6a,9-diyl)bis(methylene)bis(octadeca-9,12-dienoate (RJ-034) as colorless oil (20%).
- Characteristic data of RJ-033: IR (film) 3346, 3009, 2925, 2854, 1737, 1660, 1646, 1463, 1385, 1169, 1055, 967 cm−1. 1H NMR (400 MHz, CDCl3) δ 5.93 (dd, J=8.2, 3.3 Hz, 1H), 5.50-5.24 (m, 4H), 4.44 (s, 2H), 4.21 (d, J=11.4 Hz, 1H), 3.95 (d, J=11.4 Hz, 1H), 3.52 (d, J=8.1 Hz, 1H), 2.77 (t, J=6.5 Hz, 2H), 2.66 (dd, J=16.3, 8.7 Hz, 2H), 2.44 (d, J=16.4 Hz, 1H), 2.32 (t, J=7.5 Hz, 2H), 2.27 (dt, J=13.2, 3.1 Hz, 1H), 2.16 (dd, J=16.1, 10.2 Hz, 1H), 2.09-1.98 (m, 4H), 1.75 (d, J=12.5 Hz, 1H), 1.66-1.54 (m, 8H), 1.47-1.25 (m, 14H), 1.13 (td, J=13.5, 4.3 Hz, 1H), 1.04 (tdd, J=13.3, 4.1, 1.5 Hz, 1H), 0.89 (t, J=6.9 Hz, 3H), 0.87 (d, J=3.6 Hz, 3H), 0.85-0.81 (m, 2H), 0.80 (s, 3H), 0.75 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 173.8, 132.6, 132.2, 130.2, 130.0, 128.1, 127.9, 79.4, 69.5, 62.7, 56.3, 55.8, 46.4, 41.9, 39.7, 38.4, 34.3, 33.7, 33.5, 33.4, 33.2, 31.5, 29.6, 29.3, 29.1, 27.2, 25.6, 25.0, 22.9, 22.6, 21.3, 18.6, 18.4, 16.2, 14.1. HRMS (ES+) calcd for C38H64O4Na [(M+Na)+] 607.4702. found 607.4695.
- Characteristic data of RJ-034: IR (film) 3457, 3007, 2924, 2854, 1737, 1659, 1650, 1454, 1385, 1243, 1163, 1087, 1054, 723 cm−1. 1H NMR (400 MHz, CDCl3) δ 5.91 (d, J=4.7 Hz, 1H), 5.48-5.20 (m, 8H), 4.70 (d, J=11.5 Hz, 1H), 4.45 (d, J=12.8 Hz, 1H), 4.43 (s, 2H), 3.43 (t, J=8.1 Hz, 1H), 2.77 (t, J=6.5 Hz, 4H), 2.57 (dd, J=16.3, 8.8 Hz, 1H), 2.39 (d, J=16.2 Hz, 1H), 2.33 (dd, J=15.3, 7.7 Hz, 4H), 2.10-2.00 (m, 8H), 1.77 (d, J=12.1 Hz, 1H), 1.69-1.57 (m, 4H), 1.44 (d, J=13.9 Hz, 2H), 1.40-1.24 (m, 28H), 1.13 (td, J=13.4, 3.9 Hz, 2H), 0.89 (t, J=6.8 Hz, 6H), 0.86 (s, 3H), 0.83 (s, 3H), 0.80 (s, 3H).
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- To a solution of (±)-(4aR,4bS,10aR)-methyl 10a-((methoxycarbonyloxy)methyl)-4b,8,8-trimethyl-1-oxotetradecahydrophenanthrene-2-carboxylate (RJ-037) (23 mg, 0.058 mmol) in DCE (0.6 mL) was added Et2Zn (1.0 M in hexane, 93 μL, 0.093 mmol) at 0° C. After 10 minutes, CH2I2 (8 μL, 0.093 mmol) was added and the mixture was stirred at 0° C. for 2 h. Then the reaction mixture was allowed to warm to room temperature and stirred for another 14 h. The reaction contents were quenched with sat. NH4Cl(aq) (2 mL) at 0° C. and allowed to warm to room temperature. The phases were separated, and the aqueous layer was extracted with ether (3×2 mL). The organic extracts were combined, washed with sat. NaHCO3(aq) (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (gradient from 0:1→1:1 EtOAc:DCM) to afford (±)-(6aR,11aR,11bS)-methyl 6a-((methoxycarbonyl oxy)methyl)-4,4,11b-trimethyl-7-oxotetradecahydro-1H-cyclohepta[a]naphthalene-9-carboxylate (RJ-038) (16 mg, 61%) as colorless liquid. Data for RJ-038: IR (film) 2951, 2868, 2843, 1750, 1704, 1441, 1389, 1367, 1264, 1201, 1175, 1158, 1116, 961, 791 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.72 (d, J=11.2 Hz, 1H), 4.55 (d, J=11.2 Hz, 1H), 3.76 (s, 3H), 3.69 (s, 3H), 2.99 (dd, J=11.6 Hz, J=6.8 Hz, 1H), 2.87-2.73 (m, 2H), 2.14-2.04 (m, 1H), 1.84-1.72 (m, 3H), 1.72-1.61 (m, 5H), 1.61-1.57 (m, 1H), 1.52-1.42 (m, 1H), 1.42-1.28 (m, 2H), 1.28-1.21 (m, 1H), 1.15 (td, J=13.4 Hz, J=4.0 Hz, 1H), 0.94-0.89 (m, 1H), 0.87 (s, 3H), 0.87 (s, 3H), 0.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 211.2, 175.5, 155.6, 68.5, 56.4, 56.2, 54.8, 54.6, 52.1, 41.7, 39.6, 38.7, 38.5, 38.5, 33.4, 33.2, 31.5, 29.4, 21.4, 21.3, 18.6, 18.1, 16.0; HRMS (MALDI) calcd for C23H36O6 [M+Na]+: 431.2410. found: 431.2422.
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- To a solution of (±)-(6aR,11aR,11bS)-methyl 6a-((methoxycarbonyloxy)methyl)-4,4,11b-trimethyl-7-oxotetradecahydro-1H-cyclohepta[a]naphthalene-9-carboxylate (RJ-038) (8.0 mg, 0.020 mmol) in THF (0.2 mL) was added LHMDS (0.5M in THF, 59 μL, 0.029 mmol) at −78° C. The mixture was allowed to warm slowly to −20° C. over the course of 2 h. Then, cooled down to −78° C., a solution of PhSeCl (5.6 mg, 0.029 mmol) in THF (0.05 mL) was added at −78° C. After 3 h, the reaction was quenched by sat. NaHCO3(aq) (2 mL), and the aqueous layer was extracted with ether (3×2 mL). The organic extracts were combined, washed with brine (6 mL), dried over Na2SO4, and concentrated in vacuo. To a solution of the residue mentioned above in THF (0.4 mL) was added H2O2(aq) (4 μL, 0.050 mmol) and pyrine (4 μL, 0.050 mmol) at room temperature. After 2 h, the reaction was quenched by sat. NaHCO3(aq) (2 mL), and the aqueous layer was extracted with ether (3×2 mL). The organic extracts were combined, washed with brine (6 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (gradient from 1:49→1:9 EtOAc:hexanes) to give (±)-(6aR,1.1aR,11bS)-methyl 6a-((methoxycarbonyloxy)methyl)-4,4,11b-trimethyl-7-oxo-2,3,4,4a,5,6,6a,7,10,11,11a,11b-dodecahydro-1H-cyclohepta[a]naphthalene-9-carboxylate (RJ-039) (5.0 mg, 63%) as colorless oil. Data for 37: IR (film) 2952, 2865, 2845, 1752, 1721, 1693, 1440, 1389, 1363, 1264, 1210, 1134, 965, 948 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.94 (d, J=2.0 Hz, 1H), 4.70 (d, J=11.0 Hz, 1H), 4.59 (d, J=11.0 Hz, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 2.88-2.79 (m, 1H), 2.32-2.21 (m, 1H), 1.96-1.85 (m, 1H), 1.85-1.77 (m, 2H), 1.72-1.65 (m, 1H), 1.65-1.42 (m, 4H), 1.42-1.23 (m, 3H), 1.14 (td, J=13.4 Hz, J=4.0 Hz, 1H), 0.97-0.87 (m, 2H), 0.92 (s, 3H), 0.86 (s, 3H), 0.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 207.2, 167.5, 155.5, 138.1, 137.0, 69.0, 56.2, 55.5, 54.9, 54.9, 52.5, 41.7, 39.3, 38.9, 33.4, 33.2, 32.4, 29.5, 21.8, 21.4, 18.5, 18.2, 16.2; HRMS (ESI) calcd for C23H34O6 [M+Na]+: 429.2253. found: 429.2254.
-
- A solution of (±)-(6aR,11aR,11bS)-methyl 6a-((methoxycarbonyloxy)methyl)-4,4,11b-trimethyl-7-oxo-2,3,4,4a,5,6,6a,7,10,11,11a,11b-dodecahydro-1H-cyclohepta[a]naphthalene-9-carboxylate (RJ-039) (25 mg, 0.062 mmol) and DBU (19 μL, 0.124 mmol) in benzene (1.24 mL) was refluxed for 3 h. The reaction was cooled down to room temperature and then quenched by sat. NH4Cl(aq) (2 mL). The phases were separated, and the aqueous layer was extracted with EtOAc (3×2 mL). The combined organic layers were washed with sat. NaHCO3(aq) (5 mL) and brine (5 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (gradient from 1:49→1:9 EtOAc:hexanes) to give (±)-(6aR,1.1aR)-methyl 6a-((methoxycarbonyloxy)methyl)-4,4,11b-trimethyl-7-oxo-2,3,4,4a,5,6,6a,7,8,11,11a,11b-dodecahydro-1H-cyclohepta[a]naphthalene-9-carboxylate (RJ-40) (20 mg, 80%) as colorless oil. Data for RJ-40: IR (film) 2950, 2868, 2843, 1751, 1711, 1645, 1440, 1388, 1367, 1260, 1116, 1069, 963, 790 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.13-7.09 (m, 1H), 4.75 (d, J=11.2 Hz, 1H), 4.63 (d, J=11.2 Hz, 1H), 3.81 (dd, J=13.8 Hz, J=2.2 Hz, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.58 (d, J=14.0 Hz, 1H), 2.78-2.66 (m, 1H), 2.60-2.50 (m, 1H), 2.08-2.01 (m, 1H), 1.86-1.78 (m, 1H), 1.73-1.54 (m, 3H), 1.54-1.44 (m, 1H), 1.44-1.23 (m, 3H), 1.16 (td, J=13.4 Hz, J=4.0 Hz, 1H), 0.95 (s, 3H), 0.94-0.88 (m, 2H), 0.87 (s, 3H), 0.82 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 207.2, 167.0, 155.4, 144.0, 124.4, 69.3, 56.3, 55.8, 54.8, 52.2, 52.1, 41.6, 39.8, 38.3, 37.5, 33.7, 33.4, 33.1, 26.6, 21.3, 18.5, 18.5, 15.6; HRMS (EI) calcd for C23H34O6 [M+Na]+: 429.2253. found: 429.2260.
- Receptor endocytosis following arrestin recruitment and cAMP production subsequent to Gαs coupling are two major immediate downstream cellular pathways upon GLP-1 receptor activation. Arrestin recruitment will lead to proliferation and anti-apoptosis of pancreatic b-cells (30, 31), while production of cAMP will lead to insulin secretion (Doyle et al., Pharmacology & Therapeutics, 2007, 113, 546). In this example, the β-arrestin2-GFP biosensor technology (45) was employed in screening for a plant extract library to identify those that can potentiate GLP-1 to elicit receptor endocytosis. Upon agonist binding to GPCR, the cytoplasmic arrestin rapidly translocate to and bind to the activated GPCR. Arrestin also mediates receptor internalization by targeting the receptor to clathrin-coated pits (46) which is a convergent step of GPCR activation. β-arrestin2-GFP biosensor technology involved less steps of enzymatic cascade and yielded more information on the compound (45), thus was used in the initial screening of plant crude extracts and also used as an assay for purifying active compounds from plant crude extracts there would found to be active in eliciting receptor endocytosis. Following the activity of this assay, a Hedychium coronarium (HC) extract was identified to potentiate GLP-1 in arrestin mediated GLP-1 receptor endocytosis. Furthermore, compounds were isolated and purified from HC extract to homogeneity by activity directed fractionation, one of the active compounds was identified to be galanal B. Abilities of synthetic galanal B and its analogs to modulate GLP-1 dependent cAMP production in RINm5F cells and to modulate GLP-1 dependent receptor endocytosis were compared. This analysis revealed that by modifying structure of galanal B, novel compounds can be generated that selectively potentiate or suppress GLP-1 in Gαs coupling pathway. Since it is well documented that type II diabetes still retain their ability to secret GLP-1 (43,44), it is expected that compound positively modulates GLP-1 by increasing the potency of GLP-1 should be potential drug of choice in anti-diabetics.
- Extraction of HC Leaves
- Dried leaves of HC (2 kg) was minced and extracted with ethanol (20 L) at room temperature with constant stirring for 2 days. The extract was filtered off and concentrated to give a residue that was suspended in 500 ml of 80% ethanol and partitioned with 500 ml of n-hexane for three times. The remaining was concentrated, suspended in 500 ml of water and partitioned with 500 ml ethyl acetate three times followed by 500 ml n-BuOH three times. 7 g of ethyl acetate fraction was chromatographed on a silica-gel column (4.5 cm×21 cm, 180 g MERCK 200-400 mesh silica gel) eluted with 1200 ml of 20% and 1200 ml of 30% hexane-EtOAc each, followed by 1600 ml of 50%, 800 ml of 80% hexane-EtOAc and 800 ml of 100% EtOAc, the column was further eluted with 800 ml each of 20% and 50% methanol: EtOAc; 200 ml was collected for each fraction.
- Chemical Synthesis of Galanal B and its Analogues
- Commercially available (±)-sclareolide (3) was selected as the starting material and readily converted, as shown in
Scheme 1, toolefin 5 in 68% yield through a two-step protocol (1, 2) and subsequently reduced by LiAlH4 to affordaldehyde 6 in 90% yield. With considerable optimization, the subjection of 6 into a solution of ylide 7 in hot toluene efficiently furnished Wittig adduct 8 as a single isomer in 85% yield. The terminal double bond of compound 8 was then epoxidized selectively by m-CPBA, giving an inseparable mixture of 9 and 10 in a ratio of 10:1. When the mixture ofepoxides Compound 11 was obtained exclusively in 60% yield with trace amount of side products originated from ring opening of oxirane. The structural connectivity of 11 was confirmed by single-crystal X-ray diffraction. DIBAL-H reduction of 11 to compound 2 (a mixture of triols 12 and 13) followed by selective oxidation of primary alcohols by TEMPO (8) furnished 1:5 ratio of galanal A and galanal B, which can be separated by column chromatography and are identical in all respect with authentic samples isolated from HC plant and the reported data (9, 10). -
Compound 2 was synthesized according to the method shown inScheme 2. - MeNHOMe.HCl (2 equiv.), Me3Al (2 equiv.), CH2Cl2, 0° C. to rt (room temperature), 85%. b) SOCl2 (5 equiv.), pyridine (10 equiv.), CH2Cl2, −78° C., 80%. c) LiAlH4 (2 equiv.), THF, rt, 90%. d) 10 (3 equiv.), toluene, reflux, 85%. e) m-CPBA (2 equiv.), CH2Cl2, rt, 85%. f) Cp2TiCl2 (2.2 equiv.), Zn (6.6 equiv.), THF, rt, 60%. g) DIBAL-H (8 equiv.), CH2Cl2, −78° C., 80%. h) TEMPO (0.2 equiv.), NCS (4 equiv.), TBACl (0.2 equiv.), NaHCO3, K2CO3, CH2Cl2, rt, 70%).
- Receptor Endocytosis Assay
- U2OS osteosarcoma cell line stably expressing a β-arrestin2:GFP fusion protein was obtained from Norak Biosciences (now Molecular Devices, part of MDS Inc., Mississauga, Ontario). GLP-1 receptor expression construct was used to transfect the U2OS cell stably expressing β-arrestin2:GFP fusion protein and to obtain cell line stably co-expressing GLP-1 receptor and β-arrestin2:GFP fusion protein. High-content imaging of receptor endocytosis in cells was conducted with 0.03 mg/ml of ethanol extract from 2500 edible plant to identify potentiating activity for the GLP-1 dependent GLP-1 receptor endocytosis. Extracts were supplied at a concentration of 100 mg/ml in 100% DMSO. Three replicate 384-well assay microplates were plated with U2OS cells stably expressing GFP-β-arrestin2 fusion protein and the GLP-1 receptor at a density of 3,000 cells per well. Aliquots of 2.5 μL of 10× stocks of plant extract in phenol red free MEM containing 1, 0.3, or 0.1 mg/ml of plant extract plus 40 nM of GLP-1 were transferred to each well of the cell assay plate, which contained 22.5 μL of phenol red free MEM. The 3 cell assay plates were incubated at room temperature for 60 min before fixation with 2% formaldehyde and labeling of the cell nuclei with 5 μg/mL of the DNA-binding dye Hoechst 33342 (Molecular Probes, Eugene, Oreg.) for 1 hr. Plates were washed with PBS twice and sealed and could be stored at 4° C. The final concentration of the extract in the cell plate was 0.1, 0.03 and 0.001 mg/ml, and the final DMSO concentration was 1%.
- Bioluminescence Resonance Energy Transfer (BRET) Assay
- BRET assays were performed to examine the effect of candidate GLP-1 receptor modulators on the intracellular cAMP levels in RINm5F cells (an insulin-secreting cell line), following routine technology. See, e.g., Bertrand et al., J. Recept Signal Transduct Res., 2002, 22(1-4):533-541; Barak et al., Mol. Pharmacol., 74(3):585-594 (2008); U.S. Pat. No. 8,647,887, and WO1999066324.
- Imaging and Analysis
- Images and data of the cells were performed according to reported methods (51), using an ArrayScan® VTI HCS Reader (Cellomics, Inc. Pittsburgh, Pa.). Appropriate filter sets for detection of the 2 fluorophores were used, and the different fluorescent signals were recorded in 2 different image collection channels of the ARRAYSCAN VTI HCS Reader (i.e.,
channel 1 contained the blue fluorescent Hoechst 33342-labeled nuclear images, andchannel 2 contained the green fluorescent GFP-β-arrestin images). A 20×0.4 numerical aperture microscope objective was used for the imaging, 3 fields were imaged per well, and CELLOMICS's Spot Detector BIOAPPLICATION was used to acquire and analyze the images. For these experiments, the Spot Detector BIOAPPLICATION used the Hoechst-labeled nuclei to identify individual cells and then automatically counted and analyzed the GFP-labeled spots associate with each cell. In addition to the number of spots and the sum of their areas and pixel intensities, the BIOAPPLICATION also reports properties of the individual nuclei such as their area. The extent of receptor endocytosis response was expressed as % of that elicited by 1 μM of GLP-1. - One unit of activity is defined as the activity that will reach 50% of maximal response in a well of 384-well plate.
- Primary Screening Herb Ethanol Extracts that are Able to Potentiate GLP-1 Signaling
- To identify dietary molecules that could potentiate GLP-1 dependent receptor signaling, an ethanol extract library consisting 2500 edible plants was screened using β-arrestin2-GFP biosensor technology which is based on the observation that the β-arrestin2 binding of an activated receptor is a convergent step of GPCR signaling (45, 46). By monitoring the binding of β-arrestin2-GFP to the activated GLP-1 receptor and the following β-arrestin-mediated internalization of the activated receptors to clathrin-coated pits, a dose dependent activation of GLP-1 receptor by GLP-1 was observed. In addition, these processes can be visualized from its image (52), thus easily exclude false positive hits. As shown in
FIG. 1 , GLP1 (7-37) activatesGLP 1 receptor dependent β-arrestin2 translocation in a dose dependent and saturable manner, and the EC50 was measured to be 10 nM of GLP-1. This analysis demonstrated that 4 nM of GLP1 (7-37) is able to activate GLP-1 receptor to the level of 10 to 20% of the maximal response by 1 μM of the peptide. To screen for extract that acts as a modulator to potentiate GLP-1 concentration dependent GLP1 receptor endocytosis, 0.1 mg/ml of plant ethanol extract was used to test its ability to enhance the agonistic effect of 4 nM of GLP-1 (7-37) on cells co-expressing GLP-1 receptor and β-arrestin2-GFP. 2500 herb ethanol extracts were screened for ability to enhance the GLP-1 receptor endocytosis elicited by 4 nM of GLP-1. 25 out of 2500 herb extracts were found to enhance the agonistic activity of 4 nM GLP-1 (7-37) from 20% to more than 80% of the maximal response, however, 9 out these 25 primary hits were false positive as judged by visualizing the corresponding images. The remaining 16 positive hits were tested for their selectivity to potentiate GLP-1 receptor by assaying their effect on PTHR, GIPR and BRS3 signaling. These selectivity tests revealed that 11 out these 16 positive hits will also activate PTHR or GIPR or BRS3, thus the remaining 5 plant extracts were found specifically potentiate GLP-1 receptor signaling. 4 out of these 5 plants have been documented to display hypoglycemic effect or anti-diabetic effect on rodent or on other mammalian species, HC is the only plant has not been reported for its effect on blood glucose excursion. HC ethanol extract was further subjected to characterizing its effects on the potency and efficacy of GLP-1 signaling. As shown inFIG. 2A , GFP-arrestin is evenly distributed in the cytosol of cells stably co-expresses β-arrestin1-GFP and GLP-1 receptor when the receptor is at resting stage, addition of 0.06 mg/ml of HC extract alone do not change the distribution of β-arrestin1-GFP, stimulation by 4 nM of GLP-1 leads to low level formation of vesicles contains (3-arrestin1-GFP and GLP-1 receptor in the cytosol and perinuclear region, much more vesicles of the receptor/β-arrestin1-GFP complex was observed if cell co-incubated with 4 nM GLP-1 and 0.06 mg/ml of HC extract.FIG. 2B reveals titration of GLP-1 on GLP-1 receptor activation responses as % of that stimulated by 1 μM of GLP-1, showing that activation increased as GLP-1 increased from 1.5 nM and reached saturation at 324 nM of GLP-1, revealing that GLP-1 elicits GLP-1 receptor endocytosis in a dose dependent and saturable manner. While in the presence of 0.06 mg/ml ethanol extract of HC, the receptor activation started with 0.44 nM of GLP-1 and reached saturation at a GLP-1 concentration of 10 nM. Comparison of the dose response data of GLP-1 titration revealed that EC50 was reduced from 10.7 nM to 3.8 nM and that maximal activation increased from 88.2% to 129% by the presence of 0.06 mg/ml of ethanol extract of HC. The effect of HC ethanol extract is highly dependent on the concentration of GLP-1, since HC plant extracts alone does not elicit GLP-1 receptor endocytosis, indicating that it behaves like a potentiator rather than an agonist on GLP-1 receptor. This analysis indicated HC ethanol extract potentiate GLP-1 signaling by increasing the efficacy and potency of GLP-1. Further, the potency of HC extract on GLP-1 signaling was also evaluated. A titration of HC extract was performed on the receptor endocytosis elicited by 4 nM GLP-1.FIG. 2C revealed the dose-response analysis of the titration of HC extract on receptor activation by 4 nM GLP-1; 4 nM of GLP-1 alone led to 20% of receptor activation while as the concentration of HC ethanol extract increased to 0.022 mg/ml the receptor activation increased, and when HC increased to 0.2 mg/ml the activation by 4 nM of GLP-1 was potentiated from 20% to 70%. This analysis revealed that the HC ethanol extract potentiated GLP-1 activity in a dose dependent and saturable manner with an EC50 for GLP-1 signaling around 0.038 mg/ml and that maximal potentiation stimulation up to 70% of that of maximal GLP-1 titration. The potentiation effect of HC required the presence of GLP-1 as the ethanol extract of HC alone do not elicit any receptor endocytosis and has no effect on the distribution of GFP-arrestin in U2OS cells (FIG. 1A ). - Isolation and Purification of Active Components from HC Ethanol Extract
- Since extract from HC displayed potent activity on GLP-1 elicited receptor endocytosis, the active components was isolated according to its effect to potentiate GLP-1 elicited receptor endocytosis. Solvent partition with hexane, ethyl acetate, butanol, and water revealed that most of the activity was recovered in the ethyl acetate fraction (Table 1), while little activity was noted in the layer of dH2O. There is a 6-fold increase in the affinity of the fraction to potentiate GLP-1 elicited GLP-1 receptor endocytosis in ethyl acetate fraction as the EC50 of the fraction was reduced from 0.045 mg/ml to 0.007 mg/ml. The recovery of the activity was more than 100% in this step of fractionation, indicating some of the negative activity was removed. Chromatography of the ethyl acetate fraction on silica gel resolved into 36 fractions, activity assay of each fraction showed a significant activity was recovered between
fraction 4 to fraction 12 (FIG. 3 ). These active fractions (fraction I) were pooled and subjected to reverse phase silica gel chromatography and resolved into 106 fractions (FIG. 4 ). There are 30 fractions showing activity significantly higher than that of 4 nM GLP-1 alone.Fraction 26 is one of the fractions able to potentiate GLP-1 response from 20% to 40% at a concentration of 0.0002 mg/ml and its EC50 to potentiate 4 nM of GLP-1 was measured to be EC50=0.00024 mg/ml, and its potentiation effect is selective for GLP-1 but not for PTH (FIGS. 5 A and 5B). Since this fraction displayed purity more than 90% thus was subjected to structure elucidation, and its structure turn out to be galanal B which increase the affinity of GLP-1 by 4 folds (FIG. 5 C). -
TABLE 1 Partition of ethanol extract of HC EC50 at 4 nM Specific Total Weight GLP1 Activity Activity HC Fraction (gram) (mg/ml) a(U/mg) b(U) × 103 Dried plant 1400 Ethanol extract 209.65 0.045 0.42 × 103 8.8 × 107 Hexane 33.42 0.032 1.25 × 103 4.2 × 107 Ethyl acetate 19.3 0.007 5.71 × 103 1.1 × 108 Butanol 28.6 nd nd nd dH2O 124.6 nd nd aOne arbitrary unit is defined as the activity that will induce 50% of maximal response in a well of 384-well plate with a volume of 25 μL for each well. bTotal activity is obtained by multiplying the specific activity to the total weight. - Characterization of Galanal B,
Compound 1, andCompound 2 - Galanal B,
Compound 1, andCompound 2 were synthesized as described above. Their effects on GLP-1 induced receptor endocytosis were investigated. As shown inFIG. 7 , dose response curve of GLP-1 and receptor endocytosis was left shifted by the presence of 0.003 mg/ml of these compounds. The EC50 values and efficacy of galanal B,compound 1, andcompound 2 are shown in Table 2 below. These results show that the potentiating effect of these compounds on GLP-1 dependent receptor endocytosis is highly dependent on the presence of GLP-1 since reduced levels of GLP-1 resulted in a decrease of the activity. The potentiating effects of these compounds are all blocked by GLP-1 receptor antagonist—exendin 9 (FIG. 8 ), indicating their effects are mediated via GLP-1 receptor. -
TABLE 2 Effect of galanal B, compound 1, andcompound 2 on theEC50 and efficacy of GLP-1 to elicit receptor endocytosis GLP-1 Compound 2 +Galanal B + Compound 1 +only GLP-1 GLP-1 GLP-1 EC50 (nM) 8.1 0.80 1.1 4.8 Efficacy 83.2 82 115.2 106.6 (100%) - GLP-1 receptor is coupled to Gαs and leads to generation of cAMP in pancreatic β cells, to examine if the receptor endocytosis potentiating activities of the present compounds will translate into the ability to potentiate cAMP production, the effect of these compounds on the GLP-1 induced intracellular cAMP generation in RINm5F cell was tested via a BRET assay, using a cAMP biosensor as known in the art, which monitored the bioluminescence energy transferring as intracellular cAMP level increased (53). It has been demonstrated that cAMP binding induced a remarkable conformational change of the cAMP sensor expressed in RINm5F cells and the conformational change was determined by measuring the bioluminescence resonance energy transfer between the donor and acceptor in the cAMP sensor. In the resting stage when the intracellular cAMP is minimal, a large BRET ratio was observed. When cells were incubated with GLP-1 or forskolin, an increase of the intracellular levels of cAMP and a decrease of the BRET ratio were observed. However, this dose response was eliminated by the presence of 250 μM of adenylyl cyclase inhibitor MDL 12330A. To analyze the effect of compounds on the GLP-1 elicited cAMP production, it was examined if the potency of GLP-1 be changed by the presence of galanal b,
compound 1, andcompound 2. As shown inFIG. 9A , the dose response curve of GLP-1 was left shifted by 2.5 orders of magnitude when cells were co-incubated with 0.0025 mg/ml ofcompound 2 and EC50 was reduced from 7.8 nM to 0.0025 nM. The effect ofcompound 2 on GLP-1 elicited cAMP production decreased as GLP-1 concentration reduced and was diminished when GLP-1 concentration reduced to 0.1 pM, indicating thatcompound 2 alone is not able to induce cAMP production, but to increase the potency of GLP-1 to stimulate cAMP production. The potentiating effect ofcompound 2 on GLP-1 stimulated cAMP production was blocked by the presence of GLP-1 receptor antagonist—exendin 9 (FIG. 10A ) or by MDL12330A—cyclase inhibitor (FIG. 10B ), indicating the requirement of GLP-1 receptor and production of cAMP in the potentiation bycompound 2. To measure the affinity ofcompound 2 to potentiate GLP-1 dependent cAMP production, the effect of compound concentration on the enhancement of cAMP production elicited by 3 nM of GLP-1 was titrated. As shown inFIG. 9B , the production of cAMP by 3 nM of GLP-1 increased as the concentration of compound increased and became saturated as the concentration ofcompound 2 reach 0.03 mg/ml. The affinity ofcompound 2 to enhance GLP-1 was determined to be 0.001 mg/ml. Similar dose of galanal B did not facilitate GLP-1 to stimulate cAMP production (FIG. 9A ), galanal B did not significantly affect the dose-response curve of GLP-1 and cAMP production by 3 nM of GLP-1 was not changed by galanal B up to 0.04 mg/ml (FIG. 9B ). By contrast,compound 1 remarkably suppresses GLP-1 elicited cAMP production in RINm5F cells and the dose response curve of GLP-1 on cAMP production was right shifted by almost 2 orders of magnitude, the EC50 was increased from 7.8 to 360 nM (FIG. 9A ). The affinity ofcompound 1 on GLP-1 elicited cAMP production was obtained by analyzing the dependence ofcompound 1 concentration on the cAMP production elicited by 60 nM of GLP-1. As revealed inFIG. 9C , 60 nM of GLP-1 generated cAMP more than 80% of that of saturation dose, as the concentration ofcompound 1 increased, the cAMP production reduced and reached bottom saturation at 0.003 mg/ml ofcompound 1. The affinity ofcompound 1 for GLP-1 in this assay was measured to be 0.0003 mg/ml. The effect of galanal B,compound 1 andcompound 2 on the affinity of GLP-1 to elicit cAMP production in RINm5F cells are summarized in Table 3. To examine if these modulation effects ofcompound 1 andcompound 2 is specific for GLP-1, 0.03 and 0.01 mg/ml of these compounds were included in the analysis of dose dependence of GIP and glucagon on cAMP production in RINm5F cells. As shown inFIG. 11 ,compound 1 andcompound 2 at a concentration of 0.025 mg/ml do not affect the cAMP production elicited by GIP or glucagon, indicating their modulation effects are specific for GLP-1. The above studies revealed that galanal B,compound 1, andcompound 2 are modulator without intrinsic agonistic or antagonistic activity, their actions are dependent on both GLP-1 and GLP-1 receptor. -
-
TABLE 3 Effect of compound of GLP-1 dependent cAMP production in RINm5F cells GLP-1 Compound 1* +Compound 2* +Galanal B* + only GLP-1 GLP-1 GLP-1 EC50 (nM) 7.86 365 0.0025 4.93 *Titration of GLP-1 on the production of cAMP in RINm5F cells with 0.003 mg/ml of the indicated compounds. - Plants remain either the source of or the inspiration for a significant proportion of the new small-molecule chemical entities. GLP-1 receptor mediated signaling is a major target for treatment of
type 2 diabetes, further its role in Alzheimer's disease and psoriasis is under clinical investigation. Currently GLP-1 therapeutics are GLP-1 analogs or compounds with agonistic activity which may cause serious adverse effect upon chronic use. In an attempt to find compound that function as a GLP-1 modulator, instead of agonist, HC plant was identified that displays positive modulating action on GLP-1 elicited receptor endocytosis which requires the presence of GLP-1, indicating the identified activity functions as a GLP-1 potentiator with little intrinsic agonistic activity. After activity directed fractionation and purification, the structure of one of the active compounds was found to be galanal b. The purified galanal b displayed potent activity to potentiate GLP-1 to elicit recruiting β-arrestin2 to GLP-1 receptor and the following receptor endocytosis. This activity of galanal b is specific for GLP-1 as it did not show similar effect on PTH and its cognate receptor. The effect is highly dependent on the presence of GLP-1 and is abolished by the presence of GLP-1receptor antagonist exendin 9. To confirm this activity of purified galanal B, galanal B and its modified analogs were synthesized, followed by characterizing their ability (galanal b,compound 1, and compound 2) with respect to potentiating GLP-1 in eliciting receptor endocytosis and in stimulating cAMP production. - Though galanal b,
compound 1, andcompound 2 are all able to potentiate GLP-1 to elicit receptor endocytosis in a GLP-1 and GLP-1 receptor dependent manner, their ability to modulate GLP-1 in stimulating cAMP production is quite distinct, in thatcompound 1 selectively reduce the affinity of GLP-1 by a factor of 50, galanal b is neutral, whilecompound 2 selectively potentiate the affinity of GLP-1 up to 1000 fold. This finding demonstrates thatcompound 1 negatively modulate GLP-1 induced cAMP production pathway whilecompound 2 positively modulate the same pathway, though they display comparable activity on GLP-1 elicited receptor endocytosis. It was demonstrated that these activities and selectivity are dependent on the GLP-1, GLP-1 receptor and specific for the GLP-1 signaling, as they are GLP-1 concentration dependent, are all blocked by GLP-1receptor antagonist exendin 9 and do not affect cAMP production elicited by the other incretin GIP or by glucagon. Galanal b,compound 1, andcompound 2 share similar scaffolds but are structurally distinct, the present disclosure identifies a critical chemical space of galanal b relevant to its selectivity in modulating GLP-1 receptor coupling efficiency to its intracellular receptor signaling pathway. The present data show that galanal b,compound 1, andcompound 2 can display quite distinct effect on the coupling efficiency of GLP-1 receptor to Gαs while display similar effect on the coupling efficiency to β-arrestin2. The simplest explanation for this observation is that each compound will dictate a unique conformation of receptor-GLP-1-compound complex, thus the conformation of GLP-1 receptor is highly dependent on whether galanal b,compound 1, orcompound 2 is in the complex. This is consistent with the finding that GPCR can exist in multiple active conformations, distinct conformation of the receptor is stabilized by distinct ligand structure and may lead to distinct signaling selectivity (55). The present findings raise question as how galanal b and its analogs share similar structure but stabilize quite distinct conformation of GLP-1 receptor which coupled comparably to β-arrestin-2 but display opposite coupling efficiency to the pathway of cAMP production. There are at least two possible mechanisms to account for these observations. The first explanation is that the compound may bind to and modify the structure of GLP-1 receptor such that manifest as a pathway-dependent change in the signaling capacity upon binding to its orthosteric ligand GLP-1. By binding to and modifying structural conformation of the receptor, the allosteric inhibitor of parturition (PDC 113.824) induces biased signaling when an orthosteric ligand is co-bound to the prostaglandin F2α receptor (56). Alternatively, these compounds bind to GLP-1 to form a complex with distinct conformation which will stabilize a distinct set of receptor conformation upon binding and leads to positively or negatively modulate coupling efficiency to Gαs pathway while display similarly the coupling efficiency to β-arrestin2 mediated receptor endocytosis. Subtle conformation changes in peptide agonists can lead to selective coupling of the receptor to its downstream signaling pathway. As it has been shown in the case of biased agonist for thetype 1 parathyroid hormone receptor (PTH1R) (25) and angiotensin II type 1A receptor ligands (57), subtle structure change of the peptide ligands can profoundly stabilize a distinct conformation of the receptor protein that selectively affects the coupling efficiency of a particular downstream signaling pathway. Two preliminary observations in the present communication are consistent with the second mechanism that requires the binding of these compounds to GLP-1 peptide to stabilize compound-GLP-1 complex in a distinct conformation different from that of free GLP-1. First, free GLP-1 peptide is quickly degraded by limited trypsin digestion, while galanal b protects GLP-1 from trypsin degradation. Furthermore,compound 2 potentiates GLP-1 to stimulate cAMP production in RINm5F cells, but has little effect on cAMP production by a small molecule agonist Boc5, though 1000 fold higher of Boc5 is needed to stimulate low level cAMP production in RINm5F cells. - The chronic administration of glucagon-like peptide-1 (GLP-1) analogs widely used to treat type-2 diabetes was associated with a potential risk of pancreatitis (37-41) or pancreatic/thyroid cancers (42), though with benefits far outweighing the potential risks (58). Physiologically, plasma level of GLP-1 is stringently controlled by ingestion of food and by DPP-4, the plasma level of active GLP-1 will be raised from 5 pM to 20-25
pM 15 min after glucose challenge and return tobasal level 2 hr later. However, a constant high plasma concentration of GLP-1 analogs intype 2 diabetes receive GLP-1 analogs therapy (59,60) leads to stimulating target tissues constitutively and may cause the adverse undesired consequences reported in the literatures.Compound 2 which potentiate GLP-1 dependent cAMP production by 1000 fold in RINm5F cells is a “true” positive modulator for GLP-1 because it lacks intrinsic agonistic activity as it does not elicit cAMP production in the absence of GLP-1. GLP-1 positive modulator function as a dimmer switch that amplifies the signaling depends on the plasma level of endogenous GLP-1, the intensity of activation of GLP-1 receptor is controlled by the physiologic concentration of GLP-1 secreted from intestine, thus will not stimulate target tissues constitutively. Since GLP-1 secretion intype 2 diabetes is comparable to or slightly defective as compare to healthy subject (43,44), GLP-1 positive modulator will be a potential compound to treattype 2 diabetes in the future. Positive modulator without intrinsic agonistic activity but only function to potentiate the activity of endogenous GLP-1 is expected to overcome the undesired effects by skipping the step of constitutive stimulation of the target tissues (58) associated with the chronic administration of GLP-1 analogs. - GLP-1 receptors are also expressed in extra-pancreatic tissues, and trial data suggest GLP-1RAs also have effects beyond their glycaemic actions. GLP-1 signaling has been shown to be potential target for the treatment of immune dysfunction (Ahern et al., J Eur Acad Dermatol Venereol. 2013 November; 27(11):1440-3) (15), neurodegenerative diseases and cardiovascular disorders (Seufert et al., Diabetes Obes Metab. 2013 Dec. 24. doi: 10.1111/dom.12251; Egefjord et al., Dan Med J. 2012 October; 59(10):A4519). Biological effects triggered by GLP-1 receptor often result from the activation of multiple intracellular signaling pathways. Deciphering which signaling pathways are engaged following GLP-1 receptor activation appears to be primordial to reveal their contribution in the physiological and pathological processes. The development of pathway selective GLP-1 modulators to elucidate the role of the different signaling mechanisms mediated by GLP-1 receptor activation may allow the generation of new therapeutic agents with improved efficacy and reduced side effects. In this regard, the identification of GLP-1 modulator selectively promoting insulin secretion without inducing pro-inflammatory effects would offer therapeutic benefit. For many GPCR targets, the required spectrum of signaling needed to attain optimal therapeutic benefit is currently unknown, which limits the rational selection of drug candidates. Therefore, drug discovery at these tractable targets is considerably challenging. There are evidences showing that many adverse side effects can be avoided with such pathway selective compounds and provide improved treatments. The angiotensin II type 1A receptor, the β-arrestin-biased ligand Sar1, D-Ala8 angiotensin II (TRV120027) has been shown to increase cardiac performance in anesthetized rats, whereas unbiased ligands reduce cardiac performance. There is also potential for improved PTH receptor agonists used for the treatment of osteoporosis. The β-arrestin-biased ligand (D-Trp12,Tyr34)-PTH(7-34) stimulates β-arrestin while blocking G-protein signaling and promotes anabolic bone formation in the absence of bone resorption. Screening signaling pathway selective compounds provides considerable scope for the identification of compounds that selectively target clinically useful GLP-1 signaling pathways and are more neutral or even block alternative pathways, which give rise to undesirable side effects. Given the risk of chronic usage of GLP-1 agonist in
type 2 diabetes and potentially in other disorders, creating small molecules which modulates GLP-1 signaling pathway selectivity in a potent unique manner, may dramatically accelerate the rate at which critical pathway are selected. - All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.
- From the above description, one skilled in the art can easily ascertain the essential characteristics of the present disclosure, and without departing from the spirit and scope thereof, can make various changes and modifications of the present disclosure to adapt it to various usages and conditions. For example, compounds structurally analogous the compounds described herein of this present disclosure also can be made, screened for their anti-cancer activities, and used to practice this present disclosure. Thus, other embodiments are also within the claims.
- All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference for the purposes or subject matter referenced herein.
-
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