WO2020191348A1 - Arginine gingipain inhibitors - Google Patents
Arginine gingipain inhibitors Download PDFInfo
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- WO2020191348A1 WO2020191348A1 PCT/US2020/023994 US2020023994W WO2020191348A1 WO 2020191348 A1 WO2020191348 A1 WO 2020191348A1 US 2020023994 W US2020023994 W US 2020023994W WO 2020191348 A1 WO2020191348 A1 WO 2020191348A1
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- QALSEIBHJDDTQA-UHFFFAOYSA-N CC(C)(C(N)=O)OC Chemical compound CC(C)(C(N)=O)OC QALSEIBHJDDTQA-UHFFFAOYSA-N 0.000 description 5
- 0 CC(C)(C)OC(NC(NCCC[C@@](C(COC(C(F)(F)F)C(F)(F)F)O)NC(C(C)(C)OC)=O)=*)=O Chemical compound CC(C)(C)OC(NC(NCCC[C@@](C(COC(C(F)(F)F)C(F)(F)F)O)NC(C(C)(C)OC)=O)=*)=O 0.000 description 5
- FOZXNOSJMZAOJT-IENPIDJESA-N CC(C)(C(N[C@@H](CCCN)C(COC(C(F)(F)F)C(F)(F)F)O)=O)OC Chemical compound CC(C)(C(N[C@@H](CCCN)C(COC(C(F)(F)F)C(F)(F)F)O)=O)OC FOZXNOSJMZAOJT-IENPIDJESA-N 0.000 description 1
- VQVDQGAXLPDYCW-QMMMGPOBSA-N CC(C)(C(N[C@@H](CCCNC(N)N)C(COC(C(F)(F)F)C(F)(F)F)=O)=O)OC Chemical compound CC(C)(C(N[C@@H](CCCNC(N)N)C(COC(C(F)(F)F)C(F)(F)F)=O)=O)OC VQVDQGAXLPDYCW-QMMMGPOBSA-N 0.000 description 1
- POEVWHDKPAXLDC-INIZCTEOSA-N CC(C)(C)OC(N/C(/NCCC[C@@H](C(COC(C(F)(F)F)C(F)(F)F)=O)NC(c1cccnc1)=O)=N/C(OC(C)(C)C)=O)=O Chemical compound CC(C)(C)OC(N/C(/NCCC[C@@H](C(COC(C(F)(F)F)C(F)(F)F)=O)NC(c1cccnc1)=O)=N/C(OC(C)(C)C)=O)=O POEVWHDKPAXLDC-INIZCTEOSA-N 0.000 description 1
- XSOJPRBZVJKTPI-UHFFFAOYSA-N CC(C)(C)OC(N/C(/NOC(C(F)(F)F)C(F)(F)F)=N/C(OC(C)(C)C)=O)=O Chemical compound CC(C)(C)OC(N/C(/NOC(C(F)(F)F)C(F)(F)F)=N/C(OC(C)(C)C)=O)=O XSOJPRBZVJKTPI-UHFFFAOYSA-N 0.000 description 1
- NOXQQEXPBIAJNV-ZDUSSCGKSA-N CC(C)(C)OC(NCCC[C@@H](C(COC(C(F)(F)F)C(F)(F)F)=O)NC(c1cccnc1)=O)=O Chemical compound CC(C)(C)OC(NCCC[C@@H](C(COC(C(F)(F)F)C(F)(F)F)=O)NC(c1cccnc1)=O)=O NOXQQEXPBIAJNV-ZDUSSCGKSA-N 0.000 description 1
- PVXMMQKRGKWATQ-LSLKUGRBSA-N CC(C)(C)OC(NCCC[C@@H](C(COC(C(F)(F)F)C(F)(F)F)O)NC(c1cccnc1)=O)=O Chemical compound CC(C)(C)OC(NCCC[C@@H](C(COC(C(F)(F)F)C(F)(F)F)O)NC(c1cccnc1)=O)=O PVXMMQKRGKWATQ-LSLKUGRBSA-N 0.000 description 1
- IFHALCCUSXQWDE-KRWDZBQOSA-N CC(C)(C)OC(NCCC[C@@H](C(COc(cc1)ccc1F)=O)NC(C(C)(C)OC)=O)=O Chemical compound CC(C)(C)OC(NCCC[C@@H](C(COc(cc1)ccc1F)=O)NC(C(C)(C)OC)=O)=O IFHALCCUSXQWDE-KRWDZBQOSA-N 0.000 description 1
- UNYPDKKFSSXNJQ-UHFFFAOYSA-N CC(C)(C)OC(NOC(C(F)(F)F)C(F)(F)F)=O Chemical compound CC(C)(C)OC(NOC(C(F)(F)F)C(F)(F)F)=O UNYPDKKFSSXNJQ-UHFFFAOYSA-N 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N NC(c1cccnc1)=O Chemical compound NC(c1cccnc1)=O DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- KXKKOQZLVCZWAB-VUWPPUDQSA-N NCCC[C@@H](C(COC(C(F)(F)F)C(F)(F)F)O)NC(c1cccnc1)=O Chemical compound NCCC[C@@H](C(COC(C(F)(F)F)C(F)(F)F)O)NC(c1cccnc1)=O KXKKOQZLVCZWAB-VUWPPUDQSA-N 0.000 description 1
- MTYIWDUHOPCFDY-UHFFFAOYSA-N NOC(C(F)(F)F)C(F)(F)F Chemical compound NOC(C(F)(F)F)C(F)(F)F MTYIWDUHOPCFDY-UHFFFAOYSA-N 0.000 description 1
- RHMPLDJJXGPMEX-UHFFFAOYSA-N Oc(cc1)ccc1F Chemical compound Oc(cc1)ccc1F RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/24—Y being a hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/28—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to cyano groups, e.g. cyanoguanidines, dicyandiamides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/12—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
Definitions
- Porphyromonas gingivalis has been linked to the development of periodontal disease, Alzheimer’s disease and other brain disorders, cardiovascular disease, diabetes, cancer, liver disease, kidney disease, preterm birth, arthritis, pneumonia and other disorders.
- P. gingivalis is an anaerobic asaccharolytic gram-negative rod bacterium that is known to infect the oral cavity and translocate systemically into coronary arteries, aorta, placental tissue, the brain, the kidneys, and the liver.
- the bacterium has also been identified in cancerous tissues and a mechanism has been proposed by which gingipains can trigger immortalization and metastasis. See: Khanmadhi, et al.
- gingivalis produces proteases called gingipains, including Arginine Gingipain A (RgpA), Arginine Gingipain B (RgpB) and Lysine Gingipain (Kgp).
- Gingipains contribute to many functions of the organism including its survival and virulence. Gingipains can be secreted, transported to outer membrane surfaces of P.
- gingivalis or released in outer membrane vesicles by the bacterium. Gingipains degrade a broad range of proteins (e.g., immunoglobulins, proteinase inhibitors, actin, and collagen) which can lead to cytoskeleton collapse and apoptosis in many types of cells. Recent research has demonstrated that inhibitors of gingipains can prevent P. gingivalis-induced cell death. See: Travis, et al., Adv Exp Med Biol, 2000.477: 455-65; Sheets, et al., Infect Immun, 2005.73(3): 1543-52;
- Z is selected from the group consisting of NH, CH 2 , and S;
- R 1 is selected from the group consisting of H and C 1-4 alkyl
- R 2 is selected from the group consisting of H,–CN,–OH,–OR 2a ,–C(O)R 2a , and
- R 2a is selected from the C 1-8 alkyl, C 6-10 aryl, and C 7-18 arylalkyl;
- R 3 is selected from the group consisting of C 3-8 cycloalkyl, C 3-8 alkyl,
- each R 3a is independently selected from the group consisting of halogen,–CN,–NO 2 , –N 3 ,–OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy,–N(R c ) 2 , –N + (R b )3,–( CH 2 )kC(O)R b ,–NR c (CH 2 )uC(O)R b ,–O(CH 2 )uC(O)R b ,
- each R b is independently selected from the group consisting of C 1-4 alkyl
- each R c is independently selected from the group consisting of H and C 1-8 alkyl
- each subscript k is independently selected from 0, 1, 2, 3, 4, 5, and 6;
- each subscript u is independently selected from 1, 2, 3, 4, 5, and 6;
- R 4 is selected from the group consisting of–CH 2 R 4a and–CHS(O)(R 4b ) 2 ;
- R 4a is selected from the group consisting of–O–R 5 ,–SO–R 6 ,
- 3- to 12-membered heterocyclyl and 5- to 12-membered heteroaryl, wherein 3- to 12-membered heterocyclyl is optionally substituted with one or more members independently selected from the group consisting of oxo, halogen, C 1-4 alkyl, and C 1-4 haloalkyl, and
- 5- to 12-membered heteroaryl is optionally substituted with one or more
- each R 4b is independently selected C 1-8 alkyl
- R 5 and R 6 are selected from the group consisting of phenyl, C 1-8 alkyl, C 1-8 haloalkyl, and 5- to 12-membered heteroaryl,
- phenyl is optionally substituted with 1-5 halogens, and wherein 5- to 12-membered heteroaryl is optionally substituted with one or more halogen, C 1-4 alkyl, or C 1-4 haloalkyl;
- R 4 is other than 2,3,5,6-tetrafluorophenoxymethyl.
- pharmaceutical compositions containing compounds of the disclosure, or a pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients are also provided.
- methods of inhibiting a gingipain include contacting the gingipain with an effective amount of a compound as described herein.
- methods of treating a disease or condition associated with P. gingivalis infection include administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition as described herein. DETAILED DESCRIPTION OF THE INVENTION
- the present invention provides potent nonpeptidic compounds for inhibition of arginine gingipains.
- the compounds can be used to prevent cell death, inflammation, and other pathology in a variety of diseases associated with P. gingivalis infection, including aging-related conditions such as Alzheimer’s disease.
- the term“alkyl,” by itself or as part of another substituent refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated.
- Alkyl can include any number of carbons, such as C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 .
- C 1-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc.
- Alkyl can also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted. For example,“substituted alkyl” groups can be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy. [0010] As used herein, the term“alkoxy,” by itself or as part of another substituent, refers to a group having the formula–OR, wherein R is alkyl.
- cycloalkyl by itself or as part of another substituent, refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated.
- Cycloalkyl can include any number of carbons, such as C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , and C 3-12 .
- Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
- Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2] bicyclooctane, decahydronaphthalene and adamantane.
- Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring.
- Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and norbornadiene.
- exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted.
- “substituted cycloalkyl” groups can be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.
- the term“alkylene” refers to an alkyl group, as defined above, linking at least two other groups (i.e., a divalent alkyl radical). The two moieties linked to the alkylene group can be linked to the same carbon atom or different carbon atoms of the alkylene group.
- heteroalkyl refers to an alkyl group of any suitable length and having from 1 to 3 heteroatoms such as N, O and S.
- heteroalkyl can include ethers, thioethers and alkyl-amines.
- heteroatoms can also be useful, including, but not limited to, B, Al, Si and P.
- the heteroatoms can be oxidized to form moieties such as, but not limited to,–S(O)– and–S(O) 2 – .
- the heteroatom portion of the heteroalkyl can replace a hydrogen of the alkyl group to form a hydroxy, thio, or amino group.
- the heteroatom portion can be the connecting atom, or be inserted between two carbon atoms.
- the terms“halo” and“halogen,” by themselves or as part of another substituent refer to a fluorine, chlorine, bromine, or iodine atom.
- haloalkyl refers to an alkyl group where some or all of the hydrogen atoms are replaced with halogen atoms.
- alkyl groups can have any suitable number of carbon atoms, such as C 1-8 .
- haloalkyl includes trifluoromethyl, fluoromethyl, etc.
- perfluoro can be used to define a compound or radical where all the hydrogens are replaced with fluorine.
- perfluoromethyl refers to
- the term“haloalkoxy,” by itself or as part of another substituent, refers to an alkoxy group where some or all of the hydrogen atoms are replaced with halogen atoms.
- the term“halocycloalkyl,” by itself or as part of another substituent refers to a cycloalkyl group where some or all of the hydrogen atoms are replaced with halogen atoms.
- the term“deuteroalkyl,” by itself or as part of another substituent refers to an alkyl group where some or all of the hydrogen atoms are replaced with deuterium atoms.
- deuteroalkyl groups can have any suitable number of carbon atoms, such as C 1-8 .
- the term“perdeutero” can be used to define a compound or radical where all the hydrogens are replaced with deuterium.
- the term“aryl,” by itself or as part of another substituent refers to an aromatic ring system having any suitable number of carbon ring atoms and any suitable number of rings.
- Aryl groups can include any suitable number of carbon ring atoms, such as C 6 , C 7 , C 8 , C 9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 or C 16 , as well as C 6-10 , C 6-12 , or C 6-14 .
- Aryl groups can be monocyclic, fused to form bicyclic (e.g., benzocyclohexyl) or tricyclic groups, or linked by a bond to form a biaryl group.
- Representative aryl groups include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl, having a methylene linking group.
- aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl.
- Aryl groups can be substituted or
- “substituted aryl” groups can be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.
- the term“heteroaryl,” by itself or as part of another substituent refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, O or S.
- heteroatoms can also be useful, including, but not limited to, B, Al, Si and P.
- the heteroatoms can be oxidized to form moieties such as, but not limited to,–S(O)– and–S(O) 2– .
- Heteroaryl groups can include any number of ring atoms, such as C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , or C 3-12 , wherein at least one of the carbon atoms is replaced by a heteroatom.
- heteroaryl groups can be C 5-8 heteroaryl, wherein 1 to 4 carbon ring atoms are replaced with heteroatoms; or C 5-8 heteroaryl, wherein 1 to 3 carbon ring atoms are replaced with heteroatoms; or C5-6 heteroaryl, wherein 1 to 4 carbon ring atoms are replaced with heteroatoms; or C 5-6 heteroaryl, wherein 1 to 3 carbon ring atoms are replaced with heteroatoms.
- the heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
- heteroaryl groups can also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran.
- Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.
- “substituted heteroaryl” groups can be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.
- the heteroaryl groups can be linked via any position on the ring.
- pyrrole includes 1-, 2- and 3-pyrrole
- pyridine includes 2-, 3- and 4-pyridine
- imidazole includes 1-, 2-, 4- and 5-imidazole
- pyrazole includes 1-, 3-, 4- and 5-pyrazole
- triazole includes 1-, 4- and 5-triazole
- tetrazole includes 1- and 5-tetrazole
- pyrimidine includes 2-, 4-, 5- and 6- pyrimidine
- pyridazine includes 3- and 4-pyridazine
- 1,2,3-triazine includes 4- and 5-triazine
- 1,2,4-triazine includes 3-, 5- and 6-triazine
- 1,3,5-triazine includes 2-triazine
- thiophene includes 2- and 3-thiophene
- furan includes 2- and 3-furan
- thiazole includes 2-, 4- and 5-thiazole
- isothiazole includes 3-, 4- and 5-isothiazole
- oxazole includes 2-, 4- and 5-
- heteroaryl groups include those having from 5 to 10 ring members and from 1 to 3 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran.
- Other heteroaryl groups include those having from 5 to 8 ring members and from 1 to 3
- heteroatoms such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
- Some other heteroaryl groups include those having from 9 to 12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran and bipyridine.
- heteroaryl groups include those having from 5 to 6 ring members and from 1 to 2 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
- heteroaryl groups include from 5 to 10 ring members and only nitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, and cinnoline.
- Other heteroaryl groups include from 5 to 10 ring members and only oxygen heteroatoms, such as furan and benzofuran.
- heteroaryl groups include from 5 to 10 ring members and only sulfur heteroatoms, such as thiophene and benzothiophene. Still other heteroaryl groups include from 5 to 10 ring members and at least two heteroatoms, such as imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine, and cinnoline.
- heterocyclyl refers to a saturated ring system having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, O and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can be oxidized to form moieties such as, but not limited to,–S(O)– and–S(O) 2 –.
- Heterocyclyl groups can include any number of ring atoms, such as, C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , or C 3-12 , wherein at least one of the carbon atoms is replaced by a heteroatom. Any suitable number of carbon ring atoms can be replaced with heteroatoms in the heterocyclyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4.
- the heterocyclyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane.
- groups such as aziridine, azetidine, pyrrolidine, piperidine, azepan
- heterocyclyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline.
- Heterocyclyl groups can be unsubstituted or substituted.
- substituted heterocyclyl groups can be substituted with one or more groups selected from halo, hydroxy, amino, oxo, alkylamino, amido, acyl, nitro, cyano, and alkoxy.
- the heterocyclyl groups can be linked via any position on the ring.
- aziridine can be 1- or 2-aziridine
- azetidine can be 1- or 2- azetidine
- pyrrolidine can be 1-, 2- or 3-pyrrolidine
- piperidine can be 1-, 2-, 3- or 4-piperidine
- pyrazolidine can be 1-, 2-, 3-, or 4-pyrazolidine
- imidazolidine can be 1-, 2-, 3- or 4-imidazolidine
- piperazine can be 1-, 2-, 3- or 4-piperazine
- tetrahydrofuran can be 1- or 2-tetrahydrofuran
- oxazolidine can be 2-, 3-, 4- or 5-oxazolidine
- isoxazolidine can be 2-, 3-, 4- or 5-isoxazolidine
- thiazolidine can be 2-, 3-, 4- or 5-thiazolidine
- isothiazolidine can be 2-, 3-, 4- or 5- isothiazolidine
- morpholine can be 2-, 3- or 4-morpholine.
- Heterocyclyl can also form a ring having 5 to 6 ring members and 1 to 2 heteroatoms, with representative members including, but not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.
- the term“carbonyl,” by itself or as part of another substituent refers to–C(O)–, i.e., a carbon atom double-bonded to oxygen and bound to two other groups in the moiety having the carbonyl.
- the term“amino” refers to a moiety–NR 2 , wherein each R group is H or alkyl. An amino moiety can be ionized to form the corresponding ammonium cation.
- the term“sulfonyl” refers to a moiety–SO 2 R, wherein the R group is alkyl, haloalkyl, or aryl. An amino moiety can be ionized to form the corresponding ammonium cation.“Alkylsulfonyl” refers to an amino moiety wherein the R group is alkyl.
- the term“hydroxy” refers to the moiety–OH.
- the term“cyano” refers to a carbon atom triple-bonded to a nitrogen atom (i.e., the moiety–CoN).
- the term“carboxy” refers to the moiety–C(O)OH. A carboxy moiety can be ionized to form the corresponding carboxylate anion.
- the term“amido” refers to a moiety–NRC(O)R or–C(O)NR 2 , wherein each R group is H or alkyl.
- the term“nitro” refers to the moiety–NO 2 .
- the term“substituted,” whether preceded by the term“optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
- an“optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
- substituents are generally those that result in the formation of stable or chemically feasible compounds.
- stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
- “substituted,” as used herein does not encompass replacement and/or alteration of a key functional group by which a molecule is identified, e.g., such that the“substituted” functional group becomes, through substitution, a different functional group.
- a“substituted phenyl” group must still comprise the phenyl moiety and cannot be modified by substitution, in this definition, to become, e.g., a cyclohexyl group.
- suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen;–(CH 2 ) 0-4 R a ;–(CH 2 ) 0-4 OR a ;
- Each R a is independently hydrogen; C 1-8 alkyl;–CH 2 Ph,–O(CH 2 ) 0-1 Ph; – CH 2 -(5- to 6-membered heteroaryl); C 3-8 cycloalkyl; C6-10 aryl; 4- to 10-membered heterocyclyl; or 6- to 10-membered heteroaryl; and each R a may be further substituted as described below.
- R a examples of suitable monovalent substituents on R a are independently halogen, –(CH 2 )0-2R b ;–(CH 2 )0-2OH;–(CH 2 )0-2OR b ;–(CH 2 )0-2CH(OR b ) 2 ;-CN;–N 3 ; -(CH 2 )0-2C(O)R b ; –(CH 2 ) 0-2 C(O)OH;-(CH 2 ) 0-2 C(O)OR b ;–(CH 2 ) 0-2 SR b ;–(CH 2 ) 0-2 SH; -(CH 2 ) 0-2 NH 2; , –(CH 2 )0-2NHR b ;–(CH 2 )0-2NR b
- R b is independently selected from C 1-4 alkyl;–CH 2 Ph;–O(CH 2 ) 0-1 Ph; C 3-8 cycloalkyl; C 6-10 aryl; 4- to 10-membered heterocyclyl; or 6- to 10-membered heteroaryl.
- R g is selected from hydrogen; C 1-8 alkyl, which may be substituted as defined below; C 3-8 cycloalkyl; C 6-10 aryl; 4- to 10-membered heterocyclyl; or 6- to 10-membered heteroaryl.
- Suitable divalent substituents that are bound to vicinal substitutable carbons of an“optionally substituted” group include:–O(CR b
- R b is selected from hydrogen; C 1-8 alkyl which may be substituted as defined below; C 3-8 cycloalkyl; C 6-10 aryl; 4- to 10-membered heterocyclyl; or 6- to 10-membered heteroaryl.
- suitable substituents on the alkyl group of R g include halogen; -R d ; –OH;–OR d ;–CN;-C(O)OH;–C(O)OR d ;–NH 2 ;–NHR d ;–NR d
- each R d is independently C 1-4 alkyl;–CH 2 Ph;–O(CH 2 )0-1Ph; 4- to 10-membered heterocyclyl; or 6- to 10-membered heteroaryl.
- R e is independently C 1-4 alkyl;–CH 2 Ph;–O(CH 2 )0-1Ph; 4- to 10-membered heterocyclyl; or 6- to 10-membered heteroaryl.
- suitable substituents on a substitutable nitrogen of an“optionally substituted” group include—R e ;–NR e
- R e is independently hydrogen; C 1-8 alkyl which may be substituted as defined below; C 3-8 cycloalkyl; C 6-10 aryl; 4- to 10-membered heterocyclyl; or 6- to 10-membered heteroaryl.
- R e is independently halogen;–R d ;–OH;–OR d ;–CN;–C(O)OH;–C(O)OR d ;–NH 2 ;–NHR d ;–NR d
- each R d is independently C 1-4 alkyl;–CH 2 Ph;–O(CH 2 ) 0-1 Ph; C 6-10 aryl;
- the term“pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to a subject. By“pharmaceutically acceptable,” it is meant that the excipient is compatible with the other ingredients of the formulation and is not deleterious to the recipient thereof.
- Useful pharmaceutical excipients include, but are not limited to, binders, fillers, disintegrants, lubricants, glidants, coatings, sweeteners, flavors and colors.
- the term“salt” refers to acid or base salts of the compounds of the disclosure.
- Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, and quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic.
- salts of the acidic compounds described herein are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts (such as sodium, lithium, potassium, calcium, and magnesium salts), as well as ammonium salts (such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl- ammonium salts).
- bases namely cationic salts such as alkali and alkaline earth metal salts (such as sodium, lithium, potassium, calcium, and magnesium salts), as well as ammonium salts (such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl- ammonium salts).
- cationic salts such as alkali and alkaline earth metal salts (such as sodium, lithium, potassium, calcium, and magnesium salts)
- ammonium salts such as ammonium, trimethyl-ammonium, diethylammonium, and tris-
- the neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
- the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.
- compounds which are in a prodrug form are provided.
- Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the parent compounds.
- prodrugs can be converted to the parent compounds by chemical or biochemical methods in an ex vivo environment.
- prodrugs can be slowly converted to the parent compounds when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
- P. gingivalis infection refers to the invasion and colonization of P. gingivalis in a bodily tissue such as the gums or the brain. P. gingivalis infection is frequently characterized by subsequent tissue injury and disease.
- the term“gingipain” refers to cysteine proteases expressed by P. gingivalis having trypsin-like specificity (i.e., Lys-Xaa and Arg-Xaa). Gingipains are recognized as the major virulence factors of P. gingivalis and contribute to bacterial attachment and colonization, nutrient acquisition, evasion of host defenses, and tissue invasion.
- the terms“arginine gingipain” and“Rgp” are used interchangeably to refer to the P. gingivalis arginine-specific gingipains RgpA and RgpB, classified under EC number EC 3.4.22.37.
- the protease and immunoglobulin-like domains are followed by a large C- terminal extension containing hemagglutinin-adhesin domains.
- the term“inhibiting” refers to reducing the level of activity (e.g., proteolytic activity) of an enzyme such as a gingipain which can be assessed, for example, using an in vitro assay or other suitable assay.
- Inhibition of enzyme activity caused by a particular substance can be expressed as the percentage of the enzyme activity measured in the absence of the substance under similar conditions.
- the ability of a particular substance to inhibit an enzyme can be expressed as an IC50 value, i.e., the concentration of the compound required to reduce the activity of the enzyme to 50% of its maximum activity.
- the terms“treat,”“treatment,” and“treating” refer to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., cognitive impairment), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; reduction in the rate of symptom progression; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of the symptom.
- the treatment or amelioration of symptoms can be based on any objective or subjective parameter, including, e.g., the result of a physical examination.
- the terms“effective amount” and“therapeutically effective amount” refer to a dose of a compound such as an Rgp inhibitor that inhibits the activity of a gingipain and/or produces therapeutic effects for which it is administered.
- the exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); Goodman & Gilman’s The Pharmacological Basis of
- Alzheimer's disease refers to a progressive disease of the central nervous system in humans and other mammals. It is manifested by dementia
- Alzheimer’s disease is associated with progressive neurodegeneration and characteristic pathology, namely beta amyloid plaques and tau tangles.
- subject refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like.
- primates e.g., humans
- Gingipain inhibitors [0056] Provided herein are compounds according to Formula I:
- Z is selected from the group consisting of NH, CH 2 , and S;
- R 1 is selected from the group consisting of H and C 1-4 alkyl
- R 2 is selected from the group consisting of H,–CN,–OH,–OR 2a ,–C(O)R 2a , and
- R 2a is selected from the C 1-8 alkyl, C6-10 aryl, and C7-18 arylalkyl;
- R 3 is selected from the group consisting of C 3-8 cycloalkyl, C 3-8 alkyl,
- each R 3a is independently selected from the group consisting of halogen,–CN,–NO 2 , –N 3 ,–OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy,–N(R c ) 2 , –N + (R b )3,–(CH 2 )kC(O)R b ,–NR c (CH 2 )uC(O)R b ,–O(CH 2 )uC(O)R b ,
- each R b is independently selected from the group consisting of C 1-4 alkyl
- each R c is independently selected from the group consisting of H and C 1-8 alkyl
- each subscript k is independently selected from 0, 1, 2, 3, 4, 5, and 6;
- each subscript u is independently selected from 1, 2, 3, 4, 5, and 6;
- R 4 is selected from the group consisting of–CH 2 R 4a and–CHS(O)(R 4b ) 2 ;
- R 4a is selected from the group consisting of–O–R 5 ,–SO–R 6 ,
- 3- to 12-membered heterocyclyl and 5- to 12-membered heteroaryl, wherein 3- to 12-membered heterocyclyl is optionally substituted with one or more members independently selected from the group consisting of oxo, halogen, C 1-4 alkyl, and C 1-4 haloalkyl, and
- 5- to 12-membered heteroaryl is optionally substituted with one or more
- each R 4b is independently selected C 1-8 alkyl
- R 5 and R 6 are selected from the group consisting of phenyl, C 1-8 alkyl, C 1-8 haloalkyl, and 5- to 12-membered heteroaryl,
- R 2 is H. In some embodiments, R 2 is–CN. In some embodiments, R 2 is selected from–OR 2a ,–C(O)R 2a , and–C(O)OR 2a .
- R 2a is arylalkyl (e.g., benzyloxy), which is optionally substituted with one or more substituents selected from halogen,–CN,–NO 2 ,–N 3 ,–OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, and–C(O)R 2b , wherein R 2b is C 1-8 alkyl or C 6-10 aryl.
- R 2 is substituted or unsubstituted benzyloxycarbonyl (e.g., (4-benzoyl)benzyl- oxycarbonyl).
- compounds wherein R 2 is CN,–OH,–OR 2a ,–C(O)R 2a , or–C(O)OR 2a can function as prodrugs for conversion to the corresponding compounds wherein R 2 is H (e.g., upon administration to a subject).
- R 2 is CN,–OH,–OR 2a ,–C(O)R 2a , or–C(O)OR 2a
- prodrugs for conversion to the corresponding compounds wherein R 2 is H (e.g., upon administration to a subject).
- Some embodiments of the present disclosure provide compounds having a structure according to Formula Ib:
- R 3 in compounds of Formula I, Formula Ia, or Formula Ib is selected from C 3-8 cycloalkyl, C 3-8 alkyl, C6-10 aryl, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocyclyl, each of which is optionally substituted with one or more R 3a substituents.
- R 3 can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.
- R 3 can be n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, n-pentyl, branched pentyl, n-hexyl, branched hexyl, n-heptyl, branched heptyl, n-octyl, or branched octyl.
- R 3 is C 3-8 alkyl, which is optionally substituted with one or more R 3a .
- R 3 is selected from the group consisting of C 3-8 cycloalkyl and 5- to 12-membered heteroaryl.
- R 3 is selected from unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, and unsubstituted or substituted cyclohexyl. In some embodiments, R 3 is unsubstituted or substituted isopropyl. [0062] In some embodiments, R 3 is selected from unsubstituted or substituted phenyl and unsubstituted or substituted naphthyl. In some embodiments, R 3 is selected from
- unsubstituted or substituted pyrrolyl unsubstituted or substituted pyridinyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted triazinyl, unsubstituted or substituted indolyl, unsubstituted or substituted isoindolyl, and unsubstituted or substituted quinolinyl.
- R 3 is selected from cyclopentyl and phenyl, each of which is optionally substituted with one or more R 3a substituents.
- each R 3a is independently selected from halogen,–N 3 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C1- 4 haloalkoxy, and–NR c C(O)R b .
- R 3 is cyclopentyl.
- R 3 is selected from isopropyl, cyclopentyl, phenyl, pyridin- 2-yl, pyridin-3-yl, and pyridin-4-yl, each of which is optionally substituted with one or more R 3a substituents.
- each R 3a is independently selected from halogen,–N 3 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkoxy,
- R 3 and the carbonyl moiety to which it is attached form an amino acid residue.
- amino acid residue refers to a moiety wherein the grouping R 3 C(O)– has the structure: ,
- R represents the side chain of a naturally occurring amino acid (e.g., an alanine sidechain, an arginine sidechain, an asparagine sidechain, an aspartic acid sidechain, a cysteine sidechain, a glutamine sidechain, a glutamic acid sidechain, a glycine sidechain, a histidine sidechain, an isoleucine sidechain, a leucine sidechain, a lysine sidechain, a methionine sidechain, a phenylalanine sidechain, a proline sidechain, a selenocysteine sidechain, a serine sidechain, a threonine sidechain, a tryptophan sidechain, a tyrosine sidechain, or a valine sidechain) or the side chain of a non-naturally occurring amino acid (e.g., an azidohomoalanine sidechain, a propargylglycine sidechain, a p-acetyl
- the grouping R 3 C(O)– forms an L- or D-alanine residue, an L- or D-arginine residue, an L- or D- asparagine residue, an L- or D-aspartic acid residue, an L- or D-cysteine residue, an L- or D- glutamine residue, an L- or D-glutamic acid residue, an L- or D-glycine residue, an L- or D- histidine residue, an L- or D-isoleucine residue, an L- or D-leucine residue, an L- or D-lysine residue, an L- or D-methionine residue, an L- or D-phenylalanine residue, an L- or D-proline residue, an L- or D-selenocysteine residue, an L- or D-serine residue, an L- or D-threonine residue, an L- or D-tryptophan residue, an L- or D-tyrosine residue, or an L- or D
- R 4 in compounds of Formula I, Formula Ia, or Formula Ib is –CH 2 OR 5 and R 5 is C 1-8 haloalkyl.
- R 5 can be, e.g., chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2- trichloroethyl, 2,2,2-trifluoroethyl, pentachloroethyl, pentafluoroethyl, 1,1,1,3,3,3- hexachloropropyl, 1,1,1,3,3,3-hexafluoropropyl, or the like.
- R 4 is selected from 2,2,2-trifluoroethoxy and 1,1,1,3,3,3-hexafluoroisopropoxy.
- R 3 is selected from (2-methoxy)propan-2-yl, unsubstituted phenyl, phenyl substituted with one or more halogen,–N 3 , C 1-4 haloalkoxy, and/or–NR c C(O)R b , unsubstituted pyridinyl, and pyridinyl substituted with one or more halogen,–N(R c ) 2 , and/or –N + (R b )3.
- R 4 in compounds of Formula I, Formula Ia, or Formula Ib is –CH 2 OR 5 and R 5 is 3- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more halogen, C 1-4 alkyl, or C 1-4 haloalkyl.
- heterocyclyl or heteroaryl is optionally substituted with one or more halogen, C 1-3 alkyl, or C 1-3 haloalkyl.
- R 5 can be, for example, isoxazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridinyl, oxazinyl, pyrimidinyl, pyrazinyl, pyridazinyl.
- R 4 is–O-R 5 and R 5 is selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-6-yl.
- R 4 is–O-R 5 and R 5 is selected from isoxazol-3- yl, pyridin-3-yl, pyridin-4-yl, 2,6-dimethylpyridin-5-yl, and 2-methylpyrimidin-5-yl.
- R 4 is–O-R 5
- R 5 is selected from isoxazol-3-yl, pyridin-3-yl, pyridin-4-yl, 2,6- dimethylpyridin-5-yl, and 2-methylpyrimidin-5-yl
- R 3 is selected from (2- methoxy)propan-2-yl, unsubstituted phenyl, phenyl substituted with one or more halogen, –N 3 , C 1-4 haloalkoxy, and/or–NR c C(O)R b , unsubstituted pyridinyl, and pyridinyl substituted with one or more halogen,–N(R c ) 2 , and/or–N + (R b ) 3.
- R 4 in compounds of Formula I, Formula Ia, or Formula Ib is –CH 2 OR 5 and R 5 is phenyl, which is optionally substituted with 1-5 halogens.
- R 5 in compounds of Formula I, Formula Ia, or Formula Ib is selected from 2- fluorophenoxy; 3-fluorophenoxy; 4-fluorophenoxy; 2,3-difluorophenoxy; 2,4-difluoro- phenoxy; 2,5-difluorophenoxy; 2,6-difluorophenoxy; 3,4-difluorophenoxy; 3,5-difluoro- phenoxy; 2,3,6-trifluorophenoxy; and 2,3,5-trifluorophenoxy.
- R 5a is selected from 2-fluorophenoxy; 3 fluorophenoxy; 2,3-difluorophenoxy; 2,5-difluoro- phenoxy; 2,6-difluorophenoxy; 3,5-difluorophenoxy; 2,3,6-trifluorophenoxy; and 2,3,5- trifluorophenoxy.
- R 5 is selected from 2,6-difluorophenoxy and 2,3,6-trifluorophenoxy.
- R 3 is selected from (2-methoxy)propan- 2-yl, unsubstituted phenyl, phenyl substituted with one or more halogen,–N 3 ,
- the compound is selected from the group consisting of:
- the compound is selected from the group consisting of:
- protected ornithine starting material (i) can be treated with a carboxylic acid R 3 CO 2 H, a racemization inhibitor (for example HOBt), and a dehydrating agent (for example EDAC), in an organic solvent (for example DMF), generating amide (ii).
- R 3 CO 2 H a carboxylic acid
- HOBt racemization inhibitor
- EDAC dehydrating agent
- organic solvent for example DMF
- amide (ii) a dehydrating agent
- the protected ornithine can be treated with R 3 COX, wherein X is a leaving group (for example chloride), and an organic base (for example Et3N), in an organic solvent (for example CH 2 Cl2), generating amide (ii).
- a variety of applicable carboxylic acids (R 3 CO 2 H) and derivatives thereof (R 3 COX) are commercially available, or can be prepared according to known methods.
- Amide (ii) may be converted to protected ketone (iii) by various routes.
- the amide is hydrolyzed using a strong based such as NaOH.
- the resulting carboxylic acid is then reacted with ClCO 2 Et, a tertiary amine, and diazo methane to form a diazomethyl ketone, which can then be treated with HBr to provide a bromomethyl ketone.
- the–OR moiety may be converted to a chloromethyl group in one step using ClCH 2 I and LiN(iPr) 2 .
- Bromomethyl ketones and chloromethyl ketones can be heated with substituted phenols and KF in DMF to provide aryloxymethyl ketones (iii).
- the bromomethyl or chloromethyl ketones are treated with isoxazole-5-one and KF in DMF to provide isoxazolyloxymethyl ketones (iii).
- Ketone (iii) can be reduced (e.g., using sodium borohydride) to corresponding alcohol (v) prior to reaction with carbamimidothioate (vi) to yield guanidine intermediate (vii).
- guanidine intermediate (vii) e.g., with Dess- Martin periodinane
- deprotection of resulting ketone (viii) yields product (ix).
- carbamimidothioate (vi) a dicyanoamine or salt thereof (e.g., dicyanoamino sodium) may be employed to provide intermediates and/or products wherein R 2 is cyano.
- R 2 is H
- R 2 is, for example, –C(O)R 2a or–C(O)OR 2a
- Scheme 1 Scheme 1
- protecting group refers to a chemical moiety that renders a functional group (e.g., an amino group) unreactive, but is also removable so as to restore the amino group.
- protecting groups include, but are not limited to, benzyloxy- carbonyl (Z or Cbz); 9-fluorenylmethyloxycarbonyl (Fmoc); tert-butyloxycarbonyl (Boc); allyloxycarbonyl (Alloc); p-toluene sulfonyl (Tos); 2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc); 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl (Pbf); mesityl-2-sulfonyl (Mts); 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr); ace
- hydroxynorvaline starting material (xi) can acylated as described above to generate amide (xii) which can be converted to silyl ether (xiii).
- Silyl ether (xiii) can be esterified (e.g., using diazomethane) prior to conversion to protected ketones (xv) having various R 4 groups using the routes described in conjunction with Scheme 1.
- Ketone (xv) can be reduced to the corresponding alcohol (xvi) and the silyl ether can be removed for conversion of the alcohol to a halide leaving group (e.g., using N- bromosuccinimide and triphenylphosphine) for displacement with thiourea (xviii).
- a halide leaving group e.g., using N- bromosuccinimide and triphenylphosphine
- hydroxynorleucine starting material (xxi) can be converted to nitrile (xxii), e.g., by converting the alcohol to an iodide under Appel conditions with iodine, triphenylphosphine, and imidazole prior to reaction with potassium cyanide.
- Nitrile (xxii) can then be deprotected and acylated to generate amide (xxiii) which can be converted to protected ketones (xxiv) having various R 4 groups, as described above.
- Ketone (xxiv) can be reduced to the corresponding alcohol (xxv) prior to displacement with hydroxylamine R 2 NHOH and hydrogenation.
- the resulting amidine intermediate can be reoxidized to provide product (xxvi).
- the starting materials and the intermediates of the reaction can be isolated and purified if desired using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including measuring physical constants and obtaining spectral data.
- the reactions described herein take place at atmospheric pressure over a temperature range of from about -78 °C to about 250 °C. For example, reactions can be conducted at from about 0 °C to about 125 °C, or at about room (or ambient) temperature, e.g., about 20 °C.
- reactions are conducted at about 0 °C, 20 °C, 25 °C, 90 °C, 100 °C, 110 °C, 125 °C, 150 °C, 175 °C, or 200 °C. In some embodiments, reactions are conducted starting at a first temperature (e.g., about -78 °C or about 0 °C), and allowed to warm to a higher second temperature (e.g., about 20 °C or about 25 °C).
- a first temperature e.g., about -78 °C or about 0 °C
- a higher second temperature e.g., about 20 °C or about 25 °C
- the compounds described herein are highly active Rgp inhibitors, typically exhibiting Rgp IC 50 values in the picomolar, nanomolar, or micromolar range.
- IC 50 indicates how much of a compound is needed to inhibit a given biological process (or component of a process, e.g., an enzyme, cell, cell receptor, or microorganism) by one half (50%).
- the IC50 value for a particular test compound can be measured as follows.
- Z-Arg-7-amido-4-methylcoumarin (“Z-Arg-AMC;” 40 mM in buffer) is added to all wells, and the contents are mixed. The reaction is monitored for AMC fluorescence for 15 min at 25°C, and the progress curves are automatically converted to rates by the Fluoroskan Ascent software.
- the IC50 of a compound can then be determined by constructing a dose-response curve and examining the effect of different concentrations of the compound on reversing the activity of the enzyme. From the dose-response curve, IC 50 values can be calculated for a given compound by determining the concentration needed to inhibit half of the maximum biological response of the enzyme.
- the method can also be used to assay enzymes including Kgp, trypsin, and cathepsins such as cathepsin B.
- the substrate can be succinyl-Ala-Phe-Lys-AMC.
- the buffer can contain 10 mM Tris and 10 mM CaCl2 (pH 8.0), and the substrate can be Z-Gly-Gly-Arg-AMC.
- the buffer can contain 50 mM sodium phosphate, 1 mM EDTA, and 10 mM 2-mercaptoethanol (pH 6.25), and the substrate can be Z-Arg-Arg-AMC.
- the Rgp IC 50 values for compounds disclosed herein range from about 0.01 nM to about 100 ⁇ M.
- the Rgp IC 50 value for a particular compound can range, for example, from about 0.01 nM to about 0.1 nM, or from about 0.1 nM to about 1 nM, or from about 1 nM to about 100 nM, or from about 100 nM to about 250 nM, or from about 250 nM to about 500 nM, or from about 500 nM to about 750 nM, or from about 750 nM to about 1 ⁇ M, or from about 1 ⁇ M to about 10 ⁇ M, or from about 10 ⁇ M to about 25 ⁇ M, or from about 25 ⁇ M to about 50 ⁇ M, or from about 50 ⁇ M to about 75 ⁇ M, or from about 75 ⁇ M to about 100 ⁇ M.
- the Rgp IC 50 value for a particular compound can range from about 0.01 nM to about 1 nM, or from about 0.05 nM to about 0.75 nM, or from about 0.1 nM to about 0.5 nM, from about 1 nM to about 100 nM, or from about 20 nM to about 80 nM, or from about 40 nM to about 60 nM, or from about 1 ⁇ M to about 100 ⁇ M, or from about 20 ⁇ M to about 80 ⁇ M, or from about 40 ⁇ M to about 60 ⁇ M.
- an Rgp inhibitor as disclosed herein has an RgpB IC50 of 75 nM or less.
- the Rgp inhibitor has an RgpB IC50 of 50 nM or less. In some embodiments, the Rgp inhibitor has an RgpB IC 50 of 25 nM or less. In some embodiments, the Rgp inhibitor has an RgpB IC50 of 10 nM or less. In some embodiments, the Rgp inhibitor has an RgpB IC50 of 1 nM or less. [0082] In certain embodiments, Rgp inhibitors according to the present disclosure are selective for Rgp. As used herein, a“selective” Rgp inhibitor is a compound that does not substantially affect the activity of proteases other than RgpA and RgpB when administered at a therapeutically effective dose for treating a disease or condition associated with P.
- a protease that is not substantially affected by a particular compound exhibits at least 90% of its normal enzymatic activity in the presence of the compound under physiological conditions.
- Selective Rgp inhibitors include those compounds that do not affect the activity of proteases other than Rgp when administered at a therapeutically effective dose for treating a brain disorder, periodontal disease, diabetes, a cardiovascular disease, arthritis (e.g., rheumatoid arthritis, osteoarthritis, infectious arthritis, or psoriatic arthritis), preterm birth, pneumonia, cancer, a kidney disease, a liver disease, a retinal disorder, or glaucoma associated with P. gingivalis infection.
- compositions which contain a compound of Formula I, Formula Ia, or Formula Ib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
- the pharmaceutical compositions can be prepared by any of the methods well known in the art of pharmacy and drug delivery. In general, methods of preparing the compositions include the step of bringing the active ingredient into association with a carrier containing one or more accessory ingredients.
- compositions are typically prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
- the compositions can be conveniently prepared and/or packaged in unit dosage form.
- Pharmaceutical compositions containing compounds described herein can be formulated for oral use. Suitable compositions for oral administration include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, buccal patches, oral gels, chewing gums, chewable tablets, effervescent powders, and effervescent tablets.
- compositions for oral administration can be formulated according to any method known to those of skill in the art.
- Such compositions can contain one or more agents selected from sweetening agents, flavoring agents, coloring agents, antioxidants, and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
- Tablets generally contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, including: inert diluents, such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as corn starch and alginic acid; binding agents, such as polyvinylpyrrolidone (PVP), cellulose, polyethylene glycol (PEG), starch, gelatin, and acacia; and lubricating agents such as magnesium stearate, stearic acid, and talc.
- inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, and sodium phosphate
- granulating and disintegrating agents such as corn starch and alginic acid
- the tablets can be uncoated or coated, enterically or otherwise, by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
- Tablets can also be coated with a semi-permeable membrane and optional polymeric osmogents according to known techniques to form osmotic pump compositions for controlled release.
- compositions for oral administration can be formulated as hard gelatin capsules wherein the active ingredient is optionally mixed with an inert solid diluent (such as calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules wherein the active ingredient is optionally mixed with water or an oil medium (such as peanut oil, liquid paraffin, or olive oil).
- an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin
- an oil medium such as peanut oil, liquid paraffin, or olive oil.
- Rgp inhibitors can also be administered topically as a solution, ointment, cream, gel, or suspension, as well as in mouth washes, eye-drops, intranasally-administered formulations, and the like. Still further, transdermal delivery of Rgp inhibitors can be accomplished by means of iontophoretic patches and the like.
- compositions containing Rgp inhibitors can also be in the form of a sterile injectable aqueous or oleaginous solutions and suspensions.
- Sterile injectable preparations can be formulated using non-toxic parenterally-acceptable vehicles including water, Ringer’s solution, and isotonic sodium chloride solution, and acceptable solvents such as 1,3-butane diol.
- sterile, fixed oils can be used as a solvent or suspending medium.
- any bland fixed oil can be employed including synthetic monoglycerides, diglycerides, or triglycerides.
- an Rgp inhibitor can be formulated with a polymer such as Pluronic F127 and delivered subcutaneously.
- Pluronic is a hydrogel that solidifies at body temperature and can provide extended drug delivery over periods of time lasting from days to weeks.
- Aqueous suspensions can contain one or more Rgp inhibitors in admixture with excipients including, but not limited to: suspending agents such as sodium
- Dispersible powders and granules can contain one or more Rgp inhibitors in admixture with a dispersing agent, wetting agent, suspending agent, or combinations thereof.
- Oily suspensions can be formulated by suspending an Rgp inhibitor in a vegetable oil (e.g., arachis oil, olive oil, sesame oil or coconut oil), or in a mineral oil (e.g., liquid paraffin).
- Oily suspensions can contain one or more thickening agents, for example beeswax, hard paraffin, or cetyl alcohol. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.
- the pharmaceutical compositions can also be in the form of oil-in-water emulsions.
- the oily phase can be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
- Suitable emulsifying agents can be naturally- occurring gums, such as gum acacia or gum tragacanth; naturally-occurring phospholipids, such as soy lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate; and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
- the use of hybrid molecules to promote active transport or nanoparticles can be used in certain embodiments to increase blood brain barrier transport.
- compositions can also include one or more additional active agents useful in the treatment of conditions associated with P. gingivalis infection.
- the pharmaceutical compositions contain one or more Rgp inhibitors as described herein in combination with one or more additional active agents for treatment of Alzheimer’s disease.
- Therapeutic strategies include lowering circulating levels of b-amyloid and tau (as described in more detail below), stabilizing microtubules, removing atherosclerotic plaques, modulating autophagy, modulating neurotransmitter levels, and inhibiting GABA(A) a5 receptors.
- Such therapeutics can maintain and/or restore cognitive function in subjects with Alzheimer’s disease; slow the decline of cognitive function; and promote neuroplasticity and recovery of the brain.
- Active agents that can be combined with Rgp inhibitors in pharmaceutical compositions include, but are not limited to, antibiotics (i.e., bacteriocidal compounds and bacteriostatic compounds), cholinesterase inhibitors, alpha-7 nicotinic receptor modulators, serotonin modulators, NMDA modulators, A ⁇ -targeted therapies, ApoE-targeted therapies, microglia-targeted therapies, blood/brain barrier-targeted therapies, tau-targeted therapies, complement-targeted therapies, and anti-inflammatories.
- Any suitable antibiotic can be combined with one or more Rgp inhibitors in the pharmaceutical compositions.
- the pharmaceutical composition contains one more Rgp inhibitors and an antibiotic having a P.
- the P. gingivalis MIC50 of the antibiotic can be less than 20 mg/ml, less than 15 mg/ml, less than 10 mg/ml, less than 8 mg/ml, less than 6 mg/ml, or less than 5 mg/ml. In some embodiments, the P. gingivalis MIC 50 of the antibiotic is less than 1 mg/ml. In some embodiments, the P. gingivalis MIC50 of the antibiotic is less than 0.2 mg/ml.
- bacteriocidal and bacteriostatic compounds include, but are not limited to: quinolones (e.g., moxifloxacin, gemifloxacin, ciprofloxacin, oflaxacin, trovafloxacin, sitafloxacin, and the like), b-lactams (e.g., penicillins such as amoxicillin, amoxacilin- clavulanate, piperacillin-tazobactam, penicillin G, and the like; and cephalosporins such as ceftriaxone and the like), macrolides (e.g., erythromycin, azithromycin, clarithromycin, and the like), carbapenems (e.g., doripenem, imipenem, meropinem, ertapenem, and the like), thiazolides (e.g., tizoxanidine, nitazoxanidine, RM 4807, RM 4809, and the like
- Bacteriocidal and bacteriostatic compounds also include agents that inhibit or otherwise interfere with formation of biofilms by anaerobic, gram-negative bacteria; such agents include oxantel, morantel, thiabendazole, and the like.
- Compositions can contain one or more Rgp inhibitors as described herein with one or more (e.g., two, three, four, five, six, or more) bacteriocidal/bacteriostatic compounds.
- Compositions containing bacteriocidal/bacteriostatic compounds can further contain a chlorhexidine (e.g., chlorhexidine digluconate) alone or in combination with a zinc compound (e.g., zinc acetate), can also be used in combination with the administered antibiotics.
- a chlorhexidine e.g., chlorhexidine digluconate
- a zinc compound e.g., zinc acetate
- a combination of a penicillin (e.g., amoxicillin) and metronidazole or a combination of penicillin (e.g., amoxicillin), metronidazole and a tetracycline is used.
- the antibiotic is selected from minocycline, doxycycline, metronidazole, amoxicillin, clindamycin, augmentin, satranidazole, and combinations thereof.
- suitable cholinesterase inhibitors include, but are not limited to, donepezil, donepezil/memantine, galantamine, rivastigmine, and tacrine, as well as pharmaceutically acceptable salts thereof.
- suitable serotonin modulators include, but are not limited to, idalopirdine, RVT-101, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, as well as pharmaceutically acceptable salts thereof.
- alpha-7 nicotinic receptor modulators include, but are not limited to, alpha-7 agonists such as encenicline and APN1125.
- Suitable NMDA modulators include, but are not limited to, NMDA receptor antagonists such as memantine and derivatives thereof.
- Pharmaceutical compositions can also contain active agents that are directed to biomolecular targets associated with neurological diseases. Such targets include beta amyloid peptides (also referred to as beta amyloid, abeta, or A ⁇ ), apolipoprotein E (also referred to as ApoE), and microtubule-associated tau (also referred to as tau proteins, or simply as tau).
- a ⁇ -targeted therapies include inhibitors of A ⁇ production (such as beta-secretase inhibitors, gamma-secretase inhibitors, alpha-secretase activators), inhibitors of A ⁇ aggregation, inhibitors of A ⁇ oligomerization, and up-regulators of A ⁇ clearance, among others (see, e.g., Jia, et al. BioMed Research International, 2014. Article ID 837157, doi:10.1155/2014/837157).
- a ⁇ -targeted therapies include but are not limited to, antibodies, pioglitazone, begacestat, atorvastatin, simvastatin, etazolate, and tramiprosate, as well as pharmaceutically acceptable salts thereof.
- ApoE-targeted therapies include, but are not limited to retinoid X receptor agonists (see, Cramer, et al., Science 2012.335(6075): 1503–1506) and others described by Liu et al. (Nat Rev Neurol.2013.9(2): 106–118).
- Tau-targeted therapies include, but are not limited to, methylthioninium, leuco-methylthioninium, antibodies and those described by Lee, et al. (Cold Spring Harb Perspect Med 2011; 1:a006437).
- Pharmaceutical compositions can also contain complement-targeted therapies. Such therapies target components of the complement system involved in the innate immune response.
- Complement targeted therapies include, but are not limited to, those described by Ricklin and Lambris (Nat. Biotechnology 2007.25(11): 1265-1275).
- Suitable anti-inflammatories include, but are not limited to, NSAIDs such as apazone, diclofenac, ibuprofen, indomethacin, ketoprofen, nabumetone, naproxen, piroxicam, and sulindac, as well as pharmaceutically acceptable salts thereof.
- NSAIDs such as apazone, diclofenac, ibuprofen, indomethacin, ketoprofen, nabumetone, naproxen, piroxicam, and sulindac, as well as pharmaceutically acceptable salts thereof.
- methods of inhibiting a gingipain include contacting the gingipain with an effective amount of a compound as described herein.
- the gingipain is an arginine gingipain (e.g., RgpA, RgpB, or a variant containing one or more amino acid substitutions, deletions, and/or other peptide sequence variations).
- Inhibiting the gingipain generally includes contacting the gingipain with an amount of the compound sufficient to reduce the activity of the gingipain as compared to the gingipain activity in the absence of the compound.
- contacting the gingipain with the gingipain inhibitor can result in from about 1% to about 99% gingipain inhibition (i.e., the activity of the inhibited gingipain ranges from 99% to 1% of the gingipain activity in the absence of the compound).
- the level of gingipain inhibition can range from about 1% to about 10%, or from about 10% to about 20%, or from about 20% to about 30%, or from about 30% to about 40%, or from about 40% to about 50%, or from about 50% to about 60%, or from about 60% to about 70%, or from about 70% to about 80%, or from about 80% to about 90%, or from about 90% to about 99%.
- the level of gingipain inhibition can range from about 5% to about 95%, or from about 10% to about 90%, or from about 20% to about 80%, or from about 30% to about 70%, or from about 40% to about 60%. In some embodiments, contacting the gingipain with a compound as described herein will result in complete (i.e., 100%) gingipain inhibition.
- infection with P. gingivalis and gingipain activity have been linked to the development of periodontal disease, Alzheimer’s disease and other brain disorders, cardiovascular disease, diabetes, cancer, liver disease, kidney disease, preterm birth, arthritis, pneumonia and other disorders. See: Bostanci, et al. FEMS Microbiol Lett, 2012.333(1): 1-9; Ghizoni, et al. J Appl Oral Sci, 2012.20(1): 104-12; Gatz, et al.
- Extracellular proteases produced by P. gingivalis including Arginine Gingipain A (RgpA), Arginine Gingipain B (RgpB), and Lysine Gingipain (Kgp), can also degrade a broad range of proteins in connective tissue and plasma (e.g., collagen, immunoglobulins, and proteinase inhibitors, etc.). Gingipains can enter systemic circulation and/or
- synoviocytes and chondrocytes can also cause disruption to the kallikrein-kinin cascade, blood coagulation, and host defense systems.
- Patients with gingipains in their joints and circulatory system may be subject to gingipain-induced death of synovial cells and/or chondrocytes, contributing to osteoarthritis.
- osteoarthritis refers to a chronic degenerative joint disease that results from breakdown of joint cartilage, synovial tissue, and underlying bone. It has recently been discovered that RgpB and Kgp can infiltrate human and dog joints, contributing to the development of osteoarthritis. It is believed that P.
- gingivalis and gingipains can infiltrate joint tissues via a number of routes. Gingipains can be secreted, transported to outer membrane surfaces of P. gingivalis, or released in outer membrane vesicles by the bacterium.
- P. gingivalis has previously been identified in periodontal tissues, coronary arteries, aorta, and recently, the liver—release of P. gingivalis and/or gingipains from any of these niches into the systemic circulation could result in translocation of P. gingivalis and/or gingipains to the joints. See: Travis, et al. Adv Exp Med Biol, 2000.477: 455-65; Byrne, et al. Oral Microbiol Immunol, 2009.24(6): 469-77;
- Rgp inhibitors can be used to treat diseases and conditions, such as brain disorders, caused by or otherwise affected by P. gingivalis. Accordingly, another aspect of the invention provides a method of treating a disease or condition associated with P. gingivalis infection. The method includes administering an effective amount of a compound or a composition, as described above, to a subject in need thereof.
- compounds according to the present disclosure inhibit active Rgp in the brain of a mammal, e.g., a human or an animal (e.g., a dog), and are cytoprotective or neuroprotective.
- cytoprotective it is meant that the compounds prevent aberrant changes to neurons or death of neurons.
- a brain disorder e.g., a neurodegenerative disease (e.g., Alzheimer’s disease, Down’s syndrome, epilepsy, autism, Parkinson’s disease, essential tremor, fronto-temporal dementia, progressive supranuclear palsy, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, mild cognitive impairment, age associated memory impairment, chronic traumatic encephalopathy, stroke, cerebrovascular disease, Lewy Body disease, multiple system atrophy, schizophrenia and depression, etc.), diabetes, cardiovascular disease, arthritis (e.g., rheumatoid arthritis, osteoarthritis, infectious arthritis, or psoriatic arthritis), retinal disorders (e.g., age related macular degeneration) and glaucoma.
- a neurodegenerative disease e.g., Alzheimer’s disease, Down’s syndrome, epilepsy, autism, Parkinson’s disease, essential tremor, fronto-temporal dementia, progressive supranuclear palsy, amyotrophic lateral
- the disease or condition is selected from a brain disorder, periodontal disease, diabetes, a cardiovascular disease, rheumatoid arthritis, osteoarthritis, preterm birth, pneumonia, cancer, a kidney disease, a liver disease, a retinal disorder, and glaucoma.
- the disease or condition is a brain disorder.
- the brain disorder is selected from Alzheimer’s disease, Down’s syndrome, epilepsy, autism, Parkinson’s disease, essential tremor, fronto-temporal dementia, progressive supranuclear palsy, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, mild cognitive impairment, age associated memory impairment, chronic traumatic encephalopathy, stroke, cerebrovascular disease, Lewy Body disease, multiple system atrophy, schizophrenia, and depression.
- the brain disorder is Alzheimer’s disease.
- the method further includes administering to the subject one or more active agents selected from a cholinesterase inhibitor, a serotonin modulator, an NMDA modulator, an A ⁇ targeted therapy, an ApoE targeted therapy, a microglia targeted therapy, a blood brain barrier targeted therapy, a tau targeted therapy, a complement targeted therapy, and an anti-inflammatory.
- the disease or condition is periodontal disease.
- the disease or condition is a liver disease.
- the liver disease is non-alcoholic steatohepatitis.
- the disease or condition is a retinal disorder.
- the retinal disorder is age-related macular degeneration.
- the disease or condition is cancer.
- the cancer is breast cancer, oral cancer, pancreatic cancer, or glioblastoma multiforme.
- Rgp inhibitors can be administered at any suitable dose in the methods provided herein. In general, an Rgp inhibitor is administered at a dose ranging from about 0.1 milligrams to about 1000 milligrams per kilogram of a subject’s body weight (i.e., about 0.1- 1000 mg/kg). The dose of Rgp inhibitor can be, for example, about 0.1-1000 mg/kg, or about 1-500 mg/kg, or about 25-250 mg/kg, or about 50-100 mg/kg.
- the dose of Rgp inhibitor can be about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg/kg.
- the dosages can be varied depending upon the requirements of the patient, the severity of the disorder being treated, and the particular formulation being administered.
- the dose administered to a patient should be sufficient to result in a beneficial therapeutic response in the patient.
- the size of the dose will also be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of the drug in a particular patient.
- Rgp inhibitors can be administered for periods of time which will vary depending upon the nature of the particular disorder, its severity, and the overall condition of the subject to whom the Rgp inhibitor is administered. Administration can be conducted, for example, hourly, every 2 hours, three hours, four hours, six hours, eight hours, or twice daily including every 12 hours, or any intervening interval thereof. Administration can be conducted once daily, or once every 36 hours or 48 hours, or once every month or several months. Following treatment, a subject can be monitored for changes in his or her condition and for alleviation of the symptoms of the disorder.
- the dosage of the Rgp inhibitor can either be increased in the event the subject does not respond significantly to a particular dosage level, or the dose can be decreased if an alleviation of the symptoms of the disorder is observed, or if the disorder has been remedied, or if unacceptable side effects are seen with a particular dosage.
- a therapeutically effective amount of an Rgp inhibitor can be administered to the subject in a treatment regimen comprising intervals of at least 1 hour, or 6 hours, or 12 hours, or 24 hours, or 36 hours, or 48 hours between dosages. Administration can be conducted at intervals of at least 72, 96, 120, 144, 168, 192, 216, or 240 hours (i.e., 3, 4, 5, 6, 7, 8, 9, or 10 days).
- administering is conducted in a chronic fashion over periods ranging from several months to several years. Accordingly, some embodiments provide a method of treating a disease or condition associated with P. gingivalis infection as described above, wherein the compound is administered to the subject for at least one year. In some embodiments, the compound is administered to the subject for at least 10 years. In some embodiments, the compound is administered to the subject for at least 60 years. [0118] Administration of Rgp inhibitors according to the methods provided herein typically results in the reduction of circulating levels of active Rgp in a subject and/or the reduction of active Rgp in the brain.
- administering results in at least a 20% reduction of circulating levels of active Rgp and/or at least a 20% reduction of active Rgp in the brain.
- the circulating levels of Rgp and/or the levels of Rgp in the brain are preferably reduced by from about 25% to about 95%, or from about 35% to about 95%, or from about 40% to about 85%, or from about 40% to about 80% as compared to the corresponding levels of Rgp 24 hours prior to the first administration of the Rgp inhibitor.
- Rgp inhibitors can be administered alone or in combination with one or more additional therapeutically active agents, as described above.
- the one or more additional therapeutically effective agents include, e.g.,: (i) a pharmaceutically acceptable agent which inhibits RgpA, RgpB, and/or Kgp production, translocation of RgpA, RgpB, and/or Kgp into systemic circulation or brain, and/or pathological (e.g., neurotoxic effects) of RgpA, RgpB, and/or Kgp in a mammal; (ii) an antibacterial agent which is bacteriostatic or bacteriocidal with respect to P.
- a pharmaceutically acceptable agent which inhibits RgpA, RgpB, and/or Kgp production, translocation of RgpA, RgpB, and/or Kgp into systemic circulation or brain, and/or pathological (e.g., neurotoxic effects) of RgpA, RgpB, and/or Kgp in a mammal
- an antibacterial agent which is bacteriostatic or bacteriocidal with respect to P.
- the additional therapeutically active agents also include Ab peptides level reducers, pathogenic level tau reducers, microtubule stabilizers, agents capable or removing
- compositions can contain one or more Rgp inhibitors as described herein in combination with ritonavir (RTV), which can increase bioavailability and increase blood brain barrier penetration.
- RTV ritonavir
- ritonavir is commonly combined with oral peptidic HIV protease inhibitors to increase plasma levels by inhibiting the P4503A4 enzyme and thus decreasing first-pass metabolism (see, Walmsley, et al., N Engl J Med, 2002.346(26): 2039-46).
- RTV binds to P-glycoprotein, a transmembrane efflux pump that is found in many tissues, including the blood brain barrier, allowing co- administered compounds better access to the brain (see, Marzolini, et al., Mol Pharm, 2013. 10(6): 2340-9). Therefore, a combination of RTV and Rgp inhibitors can be used to increase plasma concentrations and brain levels of the gingipain inhibitors.
- compounds described herein can be administered with natural gingipain inhibitors including melabaricone C, isolated from nutmeg or polyphenolic compounds derived from plants, such as cranberry, green tea, apple, and hops can be administered in conjunction for treatment or prevention of brain disorders.
- natural gingipain inhibitors including melabaricone C, isolated from nutmeg or polyphenolic compounds derived from plants, such as cranberry, green tea, apple, and hops can be administered in conjunction for treatment or prevention of brain disorders.
- Naturally and unnaturally occurring antimicrobial peptides including: k-casein peptide (109–137) 34, histatin 5, and CL(14-25), CL(K25A) and CL(R24A, K25A), can also be administered in conjunction with the Rgp inhibitors.
- Rgp inhibitors as described herein can be administered with antibodies targeting gingipains or other P. gingivalis proteins. Antibodies may rely on damage to the blood brain barrier for access to the brain or peripheral interference with gingipains and P. gingivalis propagation.
- Antibodies can also help to stimulate the efficacy of the immune system in clearing the bacteria.
- New or existing antibodies to RgpA, RgpB, or Kgp can be utilized including 18E6 and 7B9.
- An RgpA antibody 61BG 1.3 has previously demonstrated efficacy topically in prevention of recolonization by P. gingivalis after periodontal treatment. See, Booth et al., Infect Immun, 1996.64(2): 422-7.
- Antibodies would preferably be humanized for use in humans.
- Rgp inhibitors as described herein with one or more of the following additional therapeutically active agents or pharmaceutically acceptable salts thereof: an arginine derivative; histatin 5; baculovirus p35; a single point mutant of cowpox viral cytokine-response modifier (CrmA (Asp > Lys));
- phenylalanyl-ureido-citrullinyl-valyl-cycloarginal (FA-70C1); (acycloxy)methyl ketone (Cbz-Phe-Lys-CH 2 OCO-2,4,6-Me3Ph); peptidyl chloro-methyl ketones (e.g., chloromethyl ketone derivatives of arginine, chloromethyl ketone derivatives of lysine, and the like);
- Zn can enhance potency and selectivity of the compounds (e.g., chlorhexidine, benzamidine, etc.) used in the methods.
- An Rgp inhibitor as described herein can be administered in the same composition as an additional therapeutically active agent. Alternatively, the additional therapeutically active agent can be administered separately before, concurrently with, or after administration of the Rgp inhibitor. V. Examples Example 1. Preparation of (S)-N-(6-guanidino-1-((1,1,1,3,3,3-hexafluoropropan-2- yl)oxy)-2-oxohexan-3-yl)-2-methoxy-2-methylpropanamide (1)
- Compound 7.3 To a mixture of compound 7.2 (12.53 g, 106.10 mmol, 1eq) and HOBt (15.77 g, 116.71 mmol, 1.1eq) in DMF (300 mL) was added EDCI (22.37 g, 116.71 mmol, 1.1 eq) in one portion at 0 °C under N 2 .
- Protein 0.02 nM RgpB, isolated from culture of Porphyromonas gingivalis, as described in Pike et al. J. Biol. Chem.1994, 269(1), 406, and Potempa and Nguyen. Current Protocols in Protein Scienc.2007, 21.20.1-21.20.27.
- Each compound 10 concentrations, starting at either 100 mM or 100 nM, with lower concentrations generated by serial 3-fold dilutions. By testing a range of concentrations for each compound, the concentration required to inhibit the activity of RgpB by 50% (the“IC 50 ”) was determined. All of examples 1-17 exhibited IC 50 values between around 20 picomolar and around 375 nM.
- compounds according to the present disclosure were found to exhibit increased selectivity for Rgp over endogenous proteases such as cathepsins, in comparison to reference compound N-[(1S)-4-guanidino-1-[2-(2,3,5,6- tetrafluorophenoxy)acetyl]butyl]-cyclopentane carboxamide.
- Compound 1 of Example 1 demonstrated IC 50 values over 10 ⁇ M when screened against cathepsins K, F, B, H, V, L, and S.
- the IC 50 values of Compound 1 were around 4 to 6 orders of magnitude higher for cathepsins K, F, and B than the IC 50 values of the reference compound for cathepsins K, F, and B.
- the decreased cathepsin inhibition activity of the compounds is advantageous because cathepsins are lysosomal proteases implicated in a number of important physiological processes including MHC-II-mediated antigen presentation, bone remodeling, keratinocyte differentiation, and prohormone activation.
- the compounds of the invention can therefore be used to selectively inhibit Rgp in a subject, resulting from invasive P. gingivalis, without perturbing endogenous cathepsin activity in the subject.
- Z is selected from the group consisting of NH, CH 2 , and S;
- R 1 is selected from the group consisting of H and C 1-4 alkyl
- R 2 is selected from the group consisting of H,–CN,–OH,–OR 2a ,–C(O)R 2a , and
- R 2a is selected from the C 1-8 alkyl, C 6-10 aryl, and C 7-18 arylalkyl;
- R 3 is selected from the group consisting of C 3-8 cycloalkyl, C 3-8 alkyl,
- each R 3a is independently selected from the group consisting of halogen,–CN,–NO 2 , –N 3 ,–OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy,–N(R c ) 2 , –N + (R b )3,–(CH 2 )kC(O)R b ,–NR c (CH 2 )uC(O)R b ,–O(CH 2 )uC(O)R b ,
- each R b is independently selected from the group consisting of C 1-4 alkyl
- each R c is independently selected from the group consisting of H and C 1-8 alkyl
- each subscript k is independently selected from 0, 1, 2, 3, 4, 5, and 6;
- each subscript u is independently selected from 1, 2, 3, 4, 5, and 6;
- R 4 is selected from the group consisting of–CH 2 R 4a and–CHS(O)(R 4b ) 2 ;
- R 4a is selected from the group consisting of–O–R 5 ,–SO–R 6 ,
- 3- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl wherein 3- to 12-membered heterocyclyl is optionally substituted with one or more members independently selected from the group consisting of oxo, halogen, C 1-4 alkyl, and C 1-4 haloalkyl, and 5- to 12-membered heteroaryl is optionally substituted with one or more
- each R 4b is independently selected C 1-8 alkyl
- R 5 and R 6 are selected from the group consisting of phenyl, C 1-8 alkyl, C 1-8 haloalkyl, and 5- to 12-membered heteroaryl,
- phenyl is optionally substituted with 1-5 halogens, and wherein 5- to 12-membered heteroaryl is optionally substituted with one or more halogen, C 1-4 alkyl, or C 1-4 haloalkyl;
- R 4 is other than 2,3,5,6-tetrafluorophenoxymethyl.
- R 2 is–CN.
- R 2 is selected from the group consisting of–OR 2a ,–C(O)R 2a , and –C(O)OR 2a .
- R 2 is H. 5.
- the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of embodiments 1-13, or a
- the disease or condition is selected from the group consisting of a brain disorder, periodontal disease, diabetes, a cardiovascular disease, arthritis, elevated risk of preterm birth, pneumonia, cancer, a kidney disease, a liver disease, a retinal disorder, and glaucoma. 17. The method of embodiment 15, wherein the disease or condition is a brain disorder. 18.
- the brain disorder is selected from the group consisting of Alzheimer’s disease, Down’s syndrome, epilepsy, autism, Parkinson’s disease, essential tremor, fronto-temporal dementia, progressive supranuclear palsy, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, mild cognitive impairment, age associated memory impairment, chronic traumatic encephalopathy, stroke, cerebrovascular disease, Lewy Body disease, multiple system atrophy, schizophrenia, and depression. 19.
- the brain disorder is selected from the group consisting of Alzheimer’s disease, Down’s syndrome, epilepsy, autism, Parkinson’s disease, essential tremor, fronto-temporal dementia, progressive supranuclear palsy, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, mild cognitive impairment, age associated memory impairment, chronic traumatic encephalopathy, stroke, cerebrovascular disease, Lewy Body disease, multiple system atrophy, schizophrenia, and depression. 19.
- any one of embodiments 16-18 further comprising administering to the subject one or more active agents selected from the group consisting of a cholinesterase inhibitor, a serotonin modulator, an NMDA modulator, an A b targeted therapy, an ApoE targeted therapy, a microglia targeted therapy, a blood brain barrier targeted therapy, a tau targeted therapy, a complement targeted therapy, and an anti- inflammatory.
- active agents selected from the group consisting of a cholinesterase inhibitor, a serotonin modulator, an NMDA modulator, an A b targeted therapy, an ApoE targeted therapy, a microglia targeted therapy, a blood brain barrier targeted therapy, a tau targeted therapy, a complement targeted therapy, and an anti- inflammatory.
- 20. The method of any one of embodiments 15-19, wherein the compound is administered to the subject for at least one month. 21. The method of embodiment 20, wherein the compound is administered to the subject for at least one year. 22.
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CA3134518A CA3134518A1 (en) | 2019-03-21 | 2020-03-20 | Arginine gingipain inhibitors |
JP2021556824A JP2022526897A (en) | 2019-03-21 | 2020-03-20 | Arginine gingipain inhibitor |
EP20773768.5A EP3941586A4 (en) | 2019-03-21 | 2020-03-20 | Arginine gingipain inhibitors |
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US8486372B2 (en) * | 2007-07-27 | 2013-07-16 | Siemens Medical Solutions Usa, Inc. | Cyclic azapeptides as integrin markers and methods of using |
US9018352B2 (en) * | 2009-11-10 | 2015-04-28 | Allegro Pharmaceuticals, Inc. | Peptide compositions and therapeutic uses thereof |
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US8486372B2 (en) * | 2007-07-27 | 2013-07-16 | Siemens Medical Solutions Usa, Inc. | Cyclic azapeptides as integrin markers and methods of using |
US9018352B2 (en) * | 2009-11-10 | 2015-04-28 | Allegro Pharmaceuticals, Inc. | Peptide compositions and therapeutic uses thereof |
Non-Patent Citations (3)
Title |
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DATABASE PubChem 20 August 2012 (2012-08-20), Database accession no. 60015310 * |
MITEV ET AL.: "Inhibition of Intracellular Growth of Salmonella enterica Serovar Typhimurium in Tissue Culture by Antisense Peptide-Phosphorodiamidate Morpholino Oligomer", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 53, no. 9, 2009, pages 3700 - 3704, XP055264803, DOI: 10.1128/AAC.00099-09 * |
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