WO2005047899A2 - Utilisation d'un recepteur de lipoxine, fprl1, en tant qu'outil d'identification de composes efficaces dans le traitement de douleurs et d'inflammations - Google Patents

Utilisation d'un recepteur de lipoxine, fprl1, en tant qu'outil d'identification de composes efficaces dans le traitement de douleurs et d'inflammations Download PDF

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Publication number
WO2005047899A2
WO2005047899A2 PCT/US2004/036952 US2004036952W WO2005047899A2 WO 2005047899 A2 WO2005047899 A2 WO 2005047899A2 US 2004036952 W US2004036952 W US 2004036952W WO 2005047899 A2 WO2005047899 A2 WO 2005047899A2
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compound
group
straight chained
aryl
heteroaryl
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PCT/US2004/036952
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WO2005047899A3 (fr
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Norman Nash
Audra L. Scully
Luis Gardell
Roger Olsson
Magnus Gustafsson
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Acadia Pharmaceuticals Inc.
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Priority to CA002544983A priority Critical patent/CA2544983A1/fr
Priority to AU2004290368A priority patent/AU2004290368A1/en
Priority to BRPI0416272-2A priority patent/BRPI0416272A/pt
Priority to EP04810415A priority patent/EP1692502A2/fr
Priority to JP2006539672A priority patent/JP2007516434A/ja
Publication of WO2005047899A2 publication Critical patent/WO2005047899A2/fr
Publication of WO2005047899A3 publication Critical patent/WO2005047899A3/fr

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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
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    • G—PHYSICS
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Definitions

  • FPRLl Lipoxin Receptor
  • This tool may be utilized in compound screening, but is not limited to this application of use.
  • compounds identified to be active at this receptor would be effective therapeutics to alleviate symptoms of the immune response as a result of activation of neutrophils, leading to: vasoconstrictive, inflammatory, myeloid suppressive, cardiovascular, and gastrointestinal diseases and subsequent pain associated with these conditions.
  • Neutrophils are within the first line of host defense and, by their ability to phagocytize microbes, can protect the host from infection. However, they can also give rise to vascular injury and contribute to increased vascular permeability, edema, and subsequent release of chemoattractants. [0003] In an effort to balance the activation of neutrophils, humans and other organisms have developed a negative feedback loop that acts as a breaking signal. The orphan receptor FPRLl, which is expressed primarily on neutrophils and monocytes, could be a likely candidate for triggering this inflammatory balance and returning the cells to their resting state. [0004] FPRLl was first identified by Murphy et al.
  • the selective FPRLl compounds described here have been shown to prophylactically act as alleviators of inflammation and thus prove that the FPRLl receptor is a valuable target for drug development in reducing inflammation in such diseases as asthma, glomerulonephritis, rheumatoid arthritis and Alzheimer's disease and subsequently alleviating pain associated with these conditions.
  • Summary of the invention [0006]
  • the invention includes the use of the FPRLl receptor as a tool to identify compounds effective in treating inflammation and associated pain.
  • the invention includes the use of the FPRLl resceptor as a screening tool to identify compounds effective in treating inflammation and associated pain.
  • the invention includes the use of compounds specifically active at the FPRLl receptor as therapeutics for treating inflammation and associated pain.
  • the invention includes the prophylactic use of compounds specifically active at the FPRLl receptor as therapeutics for blocking inflammation and associated pain.
  • the invention includes a method of screening for a compound able to affect one or more activities of a FPRLl receptor comprising the steps of, a) contacting a recombinant cell with a test compound, wherein said recombinant cell comprises a recombinant nucleic acid expressing said FPRLl receptor, provided that said cell does not have functional FPRLl receptor expression from endogenous nucleic acid, and b) determining the ability of said test compound to affect one or more activities of said FPRLl receptor, and comparing said ability with the ability of said test compound to affect said one or more FPRLl receptor activities in a cell not comprising said recombinant nucleic acid; wherein said recombinant nucleic acid comprises a FPRLl receptor nucleic acid selected from the group consisting of: i) nucleic acid of SEQ ID NO 1 , ii) nucleic acid encoding the amino acid SEQ ID NO 2, iii
  • said FPRLl receptor nucleic acid encodes the amino acid sequence of a SEQ ID NO 2 derivative comprising at least 20 contiguous nucleotides which can hybridize under stringent hybridizations conditions to a complement of at least 20 contiguous nucleotides encoding the amino acid sequence of SEQ ID NO 2.
  • the invention includes a method for treating acute and chronic inflammation of any type comprising contacting an organism with an effective amount of at least one compound of Formula I, IT, or rfl, wherein the compound activates a FPRLl receptor subtype, h one aspect of this embodiment, the inflammation is associated with diabetes, viral infection, irritable bowel syndrome, amputation, cancer, bacterial infection, physical injury, including physical trauma and radiation exposure, vasoconstriction as a result of asthma, anaphylactic reactions, allergic reactions, shock, diabetes, rheumatoid arthritis, gout, psoriasis, allergic rhinitis, adult respiratory distress syndrome, Crohn's disease, endotoxin shock, traumatic shock, hemorrhagic shock, bowel ischemic shock, renal glomerular disease, benign prostatic hypertrophy, myocardial ischemia, myocardial infarction, circulatory shock, brain injury including ischaemic stroke and hemorrhagic stroke,
  • the invention includes a method of identifying a compound which is an agonist of the FPRLl receptor, the method comprising: contacting a FPRLl receptor with at least one test compound of Formula I, JJ, or HI; and determining any increase in activity level of said FPRLl receptor so as to identify a test compound which is an agonist of the FPRLl receptor.
  • the invention includes a method of identifying a compound which is an agonist of a FPRLl receptor, the method comprising: culturing cells that express said FPRLl receptor; incubating the cells or a component extracted from the cells with at least one test compound of Formula I, ⁇ , or HI; and determining any increase in activity of said FPRLl receptor so as to identify a test compound which is an agonist of a FPRLl receptor.
  • the cultured cells overexpress said FPRLl receptor.
  • the identified agonist is selective for the FPRLl receptor.
  • the invention includes a method for treating inflammation comprising contacting an individual suffering from inflammation with an effective amount of at least one compound of Formula I, II, or III, whereby one or more symptoms of the inflammation is reduced.
  • the method further comprises the step of identifying an individual in need of inflammatory treatment prior to the contacting step.
  • said compound of Formula I, ⁇ , or HI selectively activates the FPRLl receptor subtype.
  • the inflammatory response results from the activation of leukocytes, which activation comprises leukocyte migration and generation of reactive oxygen species to evoke vascular leakage or edema.
  • a tenth embodiment of the invention includes a method for treating or preventing inflammation or an inflammatory response in the subject, comprising: administering to a subject an effective anti-inflammatory amount of a compound of Formula I, H, or HI.
  • An eleventh embodiment of the invention includes a method of inducing vasodilation to treat or prevent a vasocontractive response or condition, comprising: administering to a subject an effective vasodilatory amount of a compound of Formula I, H, or HI.
  • the vasocontractive response or condition is selected from the group consisting of a renal hemodynamic disease, including glomerular disease, and a cardiovascular disease, including hypertension, myocardial infarction, and myocardial ischemia.
  • a twelfth embodiment of the invention incudes a method for antagonizing a vasoconstrictive response to a sulfidopeptide leukotriene in a subject, comprising: administering to the subject a composition of Formula I, H, or HI.
  • the vasoconstrictive response to said leukotriene is associated with a medical disorder selected from the group consisting of: asthma, I anaphylactic reactions, allergic reactions, shock, inflammation, rheumatoid arthritis, gout, psoriasis, allergic rhinitis, adult respiratory distress syndrome, Crohn's disease, endotoxin shock, traumatic shock, hemmorrhagic shock, bowel ischemic shock, renal glomerular disease, benign prostatic hypertrophy, inflammatory bowel disease, myocardial ischemia, myocardial infarction, circulatory shock, brain injury, systemic lupus erythematosus, chronic renal disease, cardiovascular disease, and hypertension
  • the vasoconstrictive response is a renal vasoconstrictive response, including mild vasoconstriction, such as chronic renal disease, and chronic severe vasoconstriction, such as glomerular kidney disease
  • a thirteenth embodiment of the invention includes a method for stimulating cell proliferation in a subject to treat or prevent myeloid suppressive disorders comprising: administering to the subject an effective amount of the compound of Formula I, H, or .
  • a fourteenth embodiment of the invention includes a compound of Formula I
  • Ri is -C 5 straight chained al ylene.
  • R is selected from the group consisting of methylene, ethylene, n-propylene, isopropylene, n-butylene, sec- butylene, tert-butylene, n-pentylene, and isopentylene.
  • R 2 is selected from the group consisting of hydrogen, hydroxy, nitro, amino, aryl, heteroaryl, -OR 7 , and -N(R ) 2 , and wherein R 7 is hydrogen or C 1 -C 10 straight chained alkyl.
  • R 7 may be hydrogen or C ⁇ -C 3 straight chained alkyl.
  • R 2 is selected from the group consisting of hydrogen, hydroxy, nitro, aryl, heteroaryl, methoxy, and ethoxy.
  • R 3 is selected from the group consisting of hydrogen, hydroxy, nitro, aryl, heteroaryl, amino, -OR 7 , and -N(R 7 ) 2 , and wherein R 7 is hydrogen or C ⁇ -C 10 straight chained alkyl.
  • R 7 is hydrogen or C ⁇ -C 3 straight chained alkyl.
  • K 3 is selected from the group consisting of hydrogen, nitro, aryl, heteroaryl.
  • R4 is selected from the group consisting of hydrogen, C1-C1 0 straight chained alkyl, hydroxy, nitro, amino, halogen, -OR 7 , and -N(R ) 2 , and wherein R7 is -C1 0 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl.
  • R is selected from the group consisting of hydrogen, C ⁇ -C 3 straight chained alkyl, hydroxy, nitro, amino, halogen, -OR 7 , and -N(R ) 2 , and R 7 is C ⁇ -C 3 straight chained alkyl optionally substituted with an aryl.
  • R 4 is selected from the group consisting of hydrogen, methyl, ethyl, hydroxy, nitro, amino, chloro, fluoro, methoxy, ethoxy, methylamino, dimethylamino, diethylamino, and benzyloxy.
  • R 5 is selected from the group consisting of hydrogen, C ⁇ -C 10 straight chained alkyl, hydroxy, nitro, amino, halogen, perhaloalkyl, -OR , and -N(R 7 ) 2 , and wherein R 7 is - o straight chained or branched alkyl optionally substituted with an aryl or heteroaryl.
  • R 5 is selected from the group consisting of hydrogen, C ⁇ -C 3 straight chained alkyl, hydroxy, nitro, amino, halogen, perhaloalkyl, -OR 7 , and -N(R 7 ) 2 , and wherein R is Ci-C 3 straight chained alkyl.
  • R 5 is selected from the group consisting of hydrogen, hydroxy, chloro, romo, trifluoromethyl, and methoxy.
  • R 6 is hydrogen.
  • R 2 and R 3 and the nitrogen to which they are attached form a fused heteroaryl or heterocyclic alkyl ring.
  • the ring may be a heterocyclic alkyl ring.
  • the heterocyclic alkyl ring may be selected from the group consisting of N-morpholine and pyrrole.
  • a fifteenth embodiment of the present invention includes a compound selected from the group consisting of
  • a sixteenth embodiment of the present invention includes a compound of Formula H
  • Ri is selected from the group consisting of oxygen and NQ, wherein Q is selected from the group consisting of hydrogen, -C 5 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl.
  • Q is Cj-C 3 straight chained or branched alkyl.
  • Q is selected from the group consisting of methyl, ethyl, and propyl.
  • Q is methyl
  • R 2 is selected from the group consisting of hydrogen, C1- 0 straight chained or branched alkyl, C 3 -C 10 cycloalkyl, and optionally substituted aryl.
  • R 2 is substituted aryl.
  • R 2 is selected from the group consisting of 4-alkylphenyl, 4-alkoxyphenyl, 4-alkoxycarbonylphenyl.
  • R 2 is selected from the group consisting of 4-methylpheynl, 4- ethoxyphenyl, and 4-ethoxycarbonylphenyl.
  • R 3 is selected from the group consisting of hydrogen, C 1 - 0 straight chained or branched alkyl, C 3 -C 10 cycloalkyl, and optionally substituted aryl.
  • R 3 is substituted aryl.
  • R 3 is selected from the group consisting of 4-alkylphenyl, 4-alkoxyphenyl, and 4-halophenyl.
  • R may be selected from the group consisting of 4- chlorophenyl, 4 bromophenyl, and 4-methoxyphenyl.
  • R 1 is selected from the group consisting of hydrogen and optionally substituted C1-C 10 straight chained or branched alkyl.
  • Ri is Ci-C 5 straight chained alkyl optionally substituted with an aryl or heteroaryl ring.
  • said aryl ring is phenyl.
  • said heteroaryl ring comprises nitrogen.
  • said heteroaryl ring is indole.
  • ⁇ is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. In a further aspect of the seventeenth embodiment said ⁇ is selected from the group consisting of methyl, indolylmethyl, benzyl, and sec-butyl.
  • R ls R 2 , the carbon to which Ri is attached, and the nitrogen to which R 2 is attached form a fused heteroaryl, or heterocyclic ring. In some versions of the preceding aspect, said heterocyclic ring is pyrolidine.
  • R 2 , R 3 , and R 5 are each independently selected from the group consisting of hydrogen, C1-C4 straight chained or branched alkyl, C 2 -C 5 straight chained or branched alkenyl, and C 2 -C 5 straight chained or branched alkynyl.
  • said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.
  • R 2 , R 3 , and R 5 are hydrogen
  • R 4 is optionally substituted aryl.
  • said aryl is phenyl.
  • said aryl is optionally substituted with halo, alkoxy, alkyl, alkylthio, and perhaloalkyl.
  • said aryl is optionally substituted with chloro, bro o, methyl, ethyl, isopropyl, methoxy, methylthio, and trifluormethyl.
  • R 4 is selected from the group consisting of 4- chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-ethylphenyl, 2,6-diisopropylphenyl, 3,4- dichlorophenyl, 4-methoxyphenyl, 4-methylmercaptophenyl, and 4-trifluoromethylphenyl.
  • R 6 is selected from the group consisting of optionally substituted C1- 0 straight chained or branched alkyl, and optionally substituted heterocyclic ring.
  • said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert- butyl, pentyl, and 1-methylbutyl.
  • said alkyl is substituted with a heterocyclic ring or a substituted amine.
  • said heterocyclic ring is morpholine.
  • said heterocyclic ring is piperidine or morpholine.
  • R 6 is selected from the group consisting of l-methyl-4-diethylaminobutyl, 2-N-morpholinoethyl, and N-benzylpiperidin-4-yl.
  • R 5 and R 6 and the nitrogen to which they are attached form an optionally substituted fused heteroaryl, or an optionally substituted heterocyclic ring, hi some versions of the preceding aspect, said heterocyclic ring is piperidine or benzopiperidine.
  • R 5 and R 6 and the nitrogen to which they are attached form a substituent selected from the group consisting of
  • An eighteenth embodiment of the present invention includes a compound selected from the group consisting of
  • the FPRLl receptor is used as a tool to identify compounds effective in treating inflammation and subsequent pain associated with an inflammatory state.
  • This receptor can be be of animal origin but in a preferred embodiment would be of human origin.
  • This receptor may be utlizied in a cellular based transfection system that would be able to detect molecules interacting with the FPRLl receptor by comparing the response elicited by FPRLl transfected cells with those devoid of the FPRLl receptor. This comparison can be through examination of binding properties of the receptor or through functional responses elicited by the cells when the cells express FPRLl and are determined to display a new phenotypic characteristic either in the presence of or absence of an additional compound.
  • This compound may thus be detrmined to be an agonist, antagonist or inverse agonist of the FPRLl receptor.
  • a method of identifying a compound which is an agonist of a FPRLl receptor comprising culturing cells that express the FPRLl receptor; incubating the cells with at least one compound and determining any increase in activity of the FPRLl receptor so as to identify a compound of which is an agonist of a FPRLl receptor.
  • the cultured cells overexpress said FPRLl receptor.
  • the identified agonist is selective for the FPRLl receptor
  • the invention relates to a method of identifying a mutation in the FPRLl receptor gene, the mutation being suspected of conferring constitutive activity on the receptor, the method comprising:
  • step (c) selecting from the cDNA in step (b) cDNA encoding the FPRLl receptor;
  • the invention relates to a method of diagnosing a disorder or condition, or a susceptibility to a disorder or condition, associated with constitutive activity of the FPRLl receptor, the method comprising:
  • the present invention relates to a test kit for detecting mutation(s) in the gene encoding the FPRLl receptor, said mutations giving rise to constitutive activity of the FPRLl receptor, the test kit comprising a nucleic acid sequence corresponding to a portion of the gene identified by the mutation identification method described above to include at least one mutation.
  • a method of identifying a compound which is an agonist of a FPRLl receptor comprising culturing cells that express the FPRLl receptor; incubating the cells with at least one compound and determining any increase in activity of the FPRLl receptor so as to identify a compound of which is an agonist of a FPRLl receptor.
  • the cultured cells overexpress said FPRLl receptor, h other embodiments, the identified agonist is selective for the FPRLl receptor.
  • a method of identifying a compound which is an antagonist or inverse agonist of a FPRLl receptor comprising culturing cells that express the FPRLl receptor; incubating the cells with at least one compound and determining any decrease in activity of the FPRLl receptor so as to identify a compound of which is an agonist of a FPRLl receptor.
  • the cultured cells overexpress said FPRLl receptor, hi other embodiments, the identified antagonist or inverse agonist is selective for the FPRLl receptor.
  • Figure 2 illustrates effects of varying dosages of Compound 7 on thermal hyperalgesia.
  • Figure 3 illustrates the %hyperalgesia observed at varying dosages of Compound 7.
  • Figure 4 illustrates the effects of varying dosages of Compound 7 on edema formation.
  • a compound of Formula I in a first aspect, disclosed herein is a compound of Formula I
  • Ri in the compound of Formula I is C Cio straight chained alkylene. h some embodiments, Ri is Ci-C 5 straight chained alkylene. hi further embodiments, Ri is selected from the group consisting of methylene, ethylene, n- propylene, isopropylene, n-butylene, sec-butylene, tert-butylene, n-pentylene, and isopentylene.
  • R in the compound of Formula I is selected from the group consisting of hydrogen, hydroxy, nitro, amino, halogen, R 7 , and -N(R 7 ) 2 , and wherein R 7 is hydrogen, aryl, heteroaryl or Ci-Cio straight chained alkyl.
  • R 2 is selected from the group consisting of hydrogen, hydroxy, nitro, halogen, and R 7 , and wherein R 7 is hydrogen or C ⁇ -C 3 straight chained alkyl.
  • R 2 is selected from the group consisting of hydrogen, hydroxy, nitro, methoxy, and ethoxy.
  • R 3 in the compound of Formula I is selected from the group consisting of hydrogen, hydroxy, nitro, amino, halogen, R 7 , and -N(R 7 ) 2 , and wherein R is hydrogen, aryl, heteroaryl or C ⁇ -C ⁇ 0 straight chained alkyl.
  • R 3 is selected from the group consisting of hydrogen, hydroxy, nitro, and - OR 7 , and wherein R 7 is hydrogen or C ⁇ -C 3 straight chained alkyl.
  • R 3 is selected from the group consisting of hydrogen, nitro, hydroxy, methoxy and ethoxy.
  • Embodiments include those in which 4 in the compound of Formula I is selected from the group consisting of hydrogen, C1-C 10 straight chained alkyl, hydroxy, nitro, amino, halogen, OR , and -N(R ) 2 , and wherein each R 7 is independently C1-C 10 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl.
  • R 4 is selected from the group consisting of hydrogen, C1-C 3 straight chained alkyl, hydroxy, nitro, amino, halogen, -OR 7 , and -N(R ) 2 , and wherein each R 7 is independently C1-C 3 straight chained alkyl optionally substituted with an aryl.
  • R. J is selected from the group consisting of hydrogen, methyl, ethyl, hydroxy, nitro, amino, chloro, fluoro, methoxy, ethoxy, methylamino, dimethylamino, diethylamino, and benzyloxy.
  • R 5 in the compound of Formula I is selected from the group consisting of hydrogen, aryl, heteroaryl, Cj-Cio straight chained alkyl, hydroxy, nitro, amino, halogen, perhaloalkyl, -OR 7 , and -N(R 7 ) 2 , and wherein each R 7 is independently C1-C 10 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl.
  • R 5 is selected from the group consisting of hydrogen, C1-C 3 straight chained alkyl, hydroxy, nitro, amino, halogen, perhaloalkyl, -OR 7 , and -N(R 7 ) 2 , and wherein each R 7 is independently C C 3 straight chained alkyl.
  • R 5 is selected from the group consisting of hydrogen, hydroxy, chloro, bromo, trifluoromethyl, and methoxy.
  • R 6 is hydrogen.
  • R 2 and R 3 and the nitrogen to which they are attached form a fused heteroaryl or heterocyclic alkyl ring, hi some embodiments, the ring is a fused heterocyclic alkyl ring, which may be a N-morpholine or pyrrole.
  • the compound of Formula I is selected from the group consisting of
  • Ri is selected from the group consisting of Ci-Cio straight chained or branched alkylene, oxygen, sulfur, NQ, CHCN, CO, OS, ONQ, SO, S(0) 2 , ONOQ wherein Q is selected from the group consisting of hydrogen, Ci-Cio straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C 2 -C ⁇ 0 straight chained or branched alkenyl optionally substituted with an aryl or heteroaryl, C 2 -Cio straight chained or branched alkynyl optionally substituted with an aryl or heteroaryl, C 3 -C ⁇ o cycloalkyl, and C 5 -C 10 cycloalkenyl; each of R , R 3 , is independently selected from the group consisting of hydrogen, Ci-Cio
  • Ri of the compound of Formula HI is selected from the group consisting of hydrogen and optionally substituted Ci-Cio straight chained or branched alkyl.
  • Ri may be C 1 -C 5 straight chained alkyl optionally substituted with an aryl or heteroaryl ring.
  • the aryl ring is phenyl, while in yet other embodiments, the heteroaryl ring comprises nitrogen. Some embodiments include those in which the heteroaryl ring is indole.
  • the alkyl group of Ri is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.
  • i is selected from the group consisting of methyl, indolylmethyl, benzyl, and sec-butyl.
  • Rj, R 2 , the carbon to which Ri is attached, and the nitrogen to which R 2 is attached form a fused heteroaryl, or heterocyclic ring.
  • the heterocyclic ring may be pyrolidine.
  • R 2 , R 3 , and R 5 of the compound of Formula HI are each independently selected from the group consisting of hydrogen, Ci-C 4 straight chained or branched alkyl, C 2 -C 5 straight chained or branched alkenyl, and C 2 -C 5 straight chained or branched alkynyl.
  • the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.
  • R 2 , R 3 , and R 5 are hydrogen.
  • 4 of the compound of Formula HI is an optionally substituted aryl.
  • the aryl is phenyl.
  • the aryl is optionally substituted with halo, alkoxy, alkyl, alkylthio, and perhaloalkyl.
  • the aryl is optionally substituted with chloro, bromo, methyl, ethyl, isopropyl, methoxy, methylthio, and trifluormethyl.
  • R 4 is selected from the group consisting of 4-chlorophenyl, 4-bromophenyl, 4- methylphenyl, 4-ethylphenyl, 2,6-diisopropylphenyl, 3,4-dichlorophenyl, 4-methoxyphenyl, 4-methylmercaptophenyl, and 4-trifluoromethylphenyl.
  • R 6 of the compound of Formula HI is selected from the group consisting of optionally substituted Ci- do straight chained or branched alkyl, and optionally substituted heterocyclic ring.
  • the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, and 1-methylbutyl.
  • the alkyl is substituted with a heterocyclic ring or a substituted amine.
  • the heterocyclic ring with which the alkyl is substituted is morpholine.
  • R 6 is an optionally substituted heterocyclic ring, which may be piperidine or morpholine.
  • R 6 is selected from the group consisting of l-methyl-4-diethylaminobutyl, 2-N-morpholinoethyl, and N-benzylpiperidin-4-yl.
  • R 5 and R 6 of the compound of Formula IH and the nitrogen to which they are attached form an optionally substituted fused heteroaryl, or an optionally substituted heterocyclic ring, hi certain embodiments, the heterocyclic ring is piperidine or benzopiperidine.
  • R 5 and R 6 and the nitrogen to which they are attached form a substituent selected from the group consisting of [0065]
  • the compound of Formula HI is selected from the group consisting of
  • pharmaceutically acceptable salt refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound disclosed herein with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • Pharmaceutical salts can also be obtained by reacting a compound disclosed herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl- D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl- D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
  • esters refers to a chemical moiety with formula -(R) n -COOR' , where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.
  • An "amide” is a chemical moiety with formula -(R) n -C(O)NHR' or -(R) n -NHC(O)R', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.
  • An amide may be an amino acid or a peptide molecule attached to a molecule of disclosed herein, thereby forming a prodrug.
  • Any amine, hydroxy, or carboxyl side chain on the compounds disclosed herein can be esterified or amidified.
  • a "prodrug” refers to an agent that is converted into the parent drag in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • prodrug a compound disclosed herein, which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • prodrug a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • aromatic refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl groups (e.g., pyridine).
  • carbocyclic aryl e.g., phenyl
  • heterocyclic aryl groups e.g., pyridine
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
  • carbocyclic refers to a compound which contains one or more covalently closed ring structures, and that the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from heterocyclic rings in which the ring backbone contains at least one atom which is different from carbon.
  • heteroaryl refers to an aromatic group which contains at least one heterocyclic ring.
  • aryl ring include, but are not limited to, benzene, and substituted benzene, such as toluene, aniline, xylene, and the like, naphthalene and substituted naphthalene, and azulene.
  • heteroaryl ring examples include, but are not limited to, furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine,
  • alkyl refers to an aliphatic hydrocarbon group.
  • the alkyl moiety may be a "saturated alkyl” group, which means that it does not contain any alkene or alkyne moieties.
  • the alkyl moiety may also be an "unsaturated alkyl” moiety, which means that it contains at least one alkene or alkyne moiety.
  • alkene refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • the alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 5 carbon atoms.
  • the alkyl group of the compounds disclosed herein may be designated as "C 1 -C alkyl” or similar designations.
  • “Ci-C 4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent group(s) is(are) one or more group(s) individually and independently selected from cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
  • alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • substituent is described as being “optionally substituted” that substituent may be substituted with one of the above substituents.
  • alkylene refers to an alkyl group, as defined here, which is a biradical and is comiected to two other moieties.
  • methylene (-CH 2 -), ethylene (-CH2CH2-), proylene (-CH 2 CH 2 CH 2 -), isopropylene (-CH 2 -CH(CH 3 )-), and isobutylene (-CI ⁇ 2 -CH(CH 3 )-CH 2 -) are examples, without limitation, of an alkylene group.
  • the substituent "R" appearing by itself and without a number designation refers to a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
  • An "O-carboxy” group refers to a RC(O)0- group, where R is as defined herein.
  • a "C-carboxy” group refers to a -C(O)0R groups where R is as defined herein.
  • An "acetyl” group refers to a -C(0)CH 3 , group.
  • a “trihalomethanesulfonyl” group refers to a X 3 CS(0) 2 - group where X is a halogen.
  • a "cyano” group refers to a -CN group.
  • An “isocyanato” group refers to a -NCO group.
  • a "thiocyanato” group refers to a -CNS group. [0086] An “isothiocyanato” group refers to a -NCS group. [0087] A “sulfmyl” group refers to a -S(0)-R group, with R as defined herein. [0088] A “S-sulfonamido” group refers to a -S(0) 2 NR, group, with R as defined herein. [0089] A "N-sulfonamido” group refers to a RS(0) 2 NH- group with R as defined herein.
  • a "trihalomethanesulfonamido” group refers to a X 3 CS(0) 2 NR- group with X and R as defined herein.
  • An "O-carbamyl” group refers to a -0C(O)-NR, group-with R as defined herein.
  • An "N-carbamyl” group refers to a R0C(O)NH- group, with R as defined herein.
  • a "C-amido” group refers to a -C(0)-NR 2 group with R as defined herein.
  • An "N-amido” group refers to a RC(0)NH- group, with R as defined herein.
  • perhaloalkyl refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.
  • Ri and R 2 and the carbons to which they are attached form a six-membered aromatic ring.
  • two substituents and the nitrogen to which they are attached form a fused heteroaryl, or heterocyclic ring; it is meant that the following structure:
  • R 2 is representative of, for example, the following structures: [0101] Unless otherwise indicated, when a substituent is deemed to be "optionally substituted,” it is meant that the substitutent is a group that may be substituted with one or more group(s) individually and independently selected from cycloalkyl, aryl, heteroaryl, heterocyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino,
  • Scheme 2 depicts the synthesis of the compounds of Formula H.
  • Scheme 3 depicts the synthesis of the compounds of Formula HI.
  • the use of the FPRLl receptor as a screening tool to identify compounds effective in treating inflammation, h some embodiments, such use may be affected through a method of screening for a compound able to affect one or more activities of a FPRLl receptor comprising the steps of, a) contacting a recombinant cell with a test compound, where the recombinant cell comprises a recombinant nucleic acid expressing said FPRLl receptor, provided that the cell does not have functional FPRLl receptor expression from endogenous nucleic acid, and b) determining the ability of the test compound to affect one or more activities of the FPRLl receptor, and comparing that ability with the ability of the test compound to affect the one or more FPRLl receptor activities in a cell not comprising the recombinant nucleic acid; where the recombinant nucleic acid comprises a FPRLl receptor nucleic acid selected from the group consisting of: i) nucleic acid of
  • the FPRLl receptor nucleic acid encodes the amino acid sequence of a SEQ ID NO:2 derivative comprising at least 20 contiguous nucleotides which can hybridize under stringent hybridizations conditions to a complement of at least 20 contiguous nucleotides encoding the amino acid sequence of SEQ ID NO:2.
  • the derivative comprises at least 50, at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500, at least 600, at least 700, at least 800, at least 900, at least 1000, at least 1100, at least 1200, at least 1300, at least 1400, at least 1500, at least 1600, at least 1700, at least 1800, at least 1900, at least 2000, at least 2100, at least 2200, at least 2300, at least 2400, or at least 2500, contiguous nucleotides which can hybridize under stringent hybridizations conditions to a complement of contiguous nucleotides encoding the amino acid sequence of SEQ ID NO:2.
  • the present disclosure is related to a method for treating acute and chronic inflammation of any type comprising contacting an organism with an effective amount of at least one compound of Formula I, H, or HI, wherein the compound activates a FPRLl receptor subtype.
  • the present disclosure is related to a method for treating inflammation comprising contacting an individual suffering from inflammation with an effective amount of at least one compound of Formula I, H, or HI, whereby one or more symptoms of the inflammation is reduced.
  • the above method further comprises the step of identifying an individual in need of inflammatory treatment prior to the contacting step.
  • the compound of Formula I, H, or HI selectively activates the FPRLl receptor subtype.
  • the present disclosure relates to a method for treating or preventing inflammation or an inflammatory response in the subject, comprising: administering to a subject an effective anti-inflammatory amount of a compound of Formula I, H, or IH.
  • the inflammatory response results from the activation of leukocytes, which activation comprises leukocyte migration and generation of reactive oxygen species to evoke vascular leakage or edema.
  • the inflammatory response is associated with rheumatoid arthritis, Azheimer's disease or asthma.
  • the inflammatory response results from physical injury, including physical trauma and radiation exposure.
  • the present disclosure relates to a method of inducing vasodilation to treat or prevent a vasocontractive response or condition, comprising: administering to a subject an ettective vasodilatory amount of a compound of Formula I, H, or HI.
  • the vasocontractive response or condition is selected from the group consisting of a renal hemodynamic disease, including glomerular disease, and a cardiovascular disease, including hypertension, myocardial infarction, and myocardial ischemia.
  • the present disclosure relates to a method for antagonizing a vasoconstrictive response to a sulfidopeptide leukotriene in a subject, comprising: administering to the subject a compound of Formula I, H, or HI.
  • the vasoconstrictive response to said leukotriene is associated with a medical disorder selected from the group consisting of: asthma, anaphylactic reactions, allergic reactions, shock, inflammation, rheumatoid artliritis, gout, psoriasis, allergic rhinitis, adult respiratory distress syndrome, Crohn's disease, endotoxin shock, traumatic shock, hemmorrhagic shock, bowel ischemic shock, renal glomerular disease, benign prostatic hypertrophy, inflammatory bowel disease, myocardial ischemia, myocardial infarction, circulatory shock, brain injury, systemic lupus erythematosus, chronic renal disease, cardiovascular disease, and hypertension.
  • a medical disorder selected from the group consisting of: asthma, anaphylactic reactions, allergic reactions, shock, inflammation, rheumatoid artliritis, gout, psoriasis, allergic rhinitis, adult respiratory distress syndrome, Crohn's
  • the vasoconstrictive response is a renal vasoconstrictive response, including mild vasoconstriction, such as chronic renal disease, and clironic severe vasoconstriction, such as glomerular kidney disease.
  • the present disclosure is related to a method for stimulating cell proliferation in a subject to treat or prevent myeloid suppressive disorders comprising: administering to the subject an effective amount of the compound of Formula I, H, or .
  • the presently disclosed methods are also directed to methods for treating acute and chronic inflammation.
  • Particular preferred embodiments of compounds for use with the methods disclosed herein are represented by COMPOUNDS 1, 2, 3, 4, 5, 6 and 7.
  • a method for treating acute and chronic pain comprising identifying an individual in need thereof, and contacting said individual with an effective amount of at least one compound of Formula I, Formula H, or Formiula HI as defined herein, whereby one or more symptoms of the pain are reduced.
  • Another aspect disclosed herein is the discovery that the disclosed FPRLl compounds are specific agonists of the FPRLl receptor. Therefore, these agonists are expected to bind to the FPRLl receptor and induce anti-inflammatory responses.
  • the agonists of FPRLl receptor described herein can be used to treat acute or chronic inflammation.
  • the compound of Formula I, Formula H, or Formula HI activates the FPRLl receptor.
  • the compound may selectively activate the FPRLl receptor subtype, but not the FPR or FPRL2 receptor.
  • activate refers to increasing the cellular function of the FPRLl receptor.
  • the receptor function is preferably the interaction with a natural binding partner.
  • natural binding partner refers to a molecule that binds to a FPRLl receptor in a cell.
  • the inflammation treated by the methods disclosed herein is associated with bacterial infection, viral infection, physical injury, including physical trauma and radiation exposure, vasoconstriction as a result of asthma, anaphylactic reactions, allergic reactions, shock, diabetes, rheumatoid arthritis, gout, psoriasis, allergic rhinitis, adult respiratory distress syndrome, Crohn's disease, endotoxin shock, traumatic shock, hemorrhagic shock, bowel ischemic shock, renal glomerular disease, benign prostatic hypertrophy, inflammatory bowel disease, myocardial ischemia, myocardial infarction, circulatory shock, brain injury including ischaemic stroke and hemorrhagic stroke, systemic lupus erythematosus, chronic renal disease, cardiovascular disease, and hypertension or chemical injury.
  • a method of identifying a compound that alleviates inflammation in a subject comprising identifying a subject suffering from inflammation; providing the subject with at least one compound of Formula I, Formula H, or Formula HI, as defined herein; and determining if said at least one compound reduces inflammation in the subject.
  • a method of identifying a compound of Formula I, Formula H, or Formula HI which is an agonist of the FPRLl receptor comprising contacting a FPRLl receptor with at least one compound of Formula I, Formula H, or Formula HI, as defined herein; and determining any increase in activity level of the FPRLl receptor so as to identify a compound of Formula I, Formula H, or Formula HI , which is an agonist of the FPRLl receptor.
  • an "agonist" is defined as a compound that increases the basal activity of a receptor (i.e. signal transduction mediated by the receptor).
  • an "antagonist” is defined as a compound, which blocks the action of an agonist on a receptor.
  • a "partial agonist” is defined as an agonist that displays limited, or less than complete, activity such that it fails to activate a receptor in vitro, functioning as an antagonist in vivo.
  • the term "subject” refers to an animal, preferably a mammal, and most preferably a human, who is the object of treatment, observation or experiment. The mammal may be selected from the group consisting of mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, primates, such as monkeys, chimpanzees, and apes, and humans.
  • terapéuticaally effective amount is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. This response may occur in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, and includes alleviation of the symptoms of the disease being treated.
  • a method of identifying a compound which is an agonist of a FPRLl receptor comprising culturing cells that express the FPRLl receptor; incubating the cells with at least one compound of Formula I, Formula H, or Formula HI as defined herein; and determining any increase in activity of the FPRLl receptor so as to identify a compound of Formula I, Formula H, or Formula HI which is an agonist of a FPRLl receptor.
  • the cultured cells overexpress said FPRLl receptor, i other embodiments, the identified agonist is selective for the FPRLl receptor.
  • a pharmaceutical composition comprising a compound of Formula I, Formula H, or Formula HI as described above, and a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.
  • pharmaceutical composition refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration.
  • compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • carrier defines a chemical compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • the term "diluent” defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound. [0135] The term "physiologically acceptable” defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.
  • compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s).
  • suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intrarnedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
  • compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.
  • compositions for use in accordance with the present disclosure thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well- known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.
  • the agents disclosed herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds disclosed herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • compositions for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination disclosed herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol
  • cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxy
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present disclosure are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.
  • gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly, concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • suitable polymeric or hydrophobic materials for example as an emulsion in an acceptable oil
  • ion exchange resins for example, ion exchange resins
  • sparingly soluble derivatives for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for the hydrophobic compounds disclosed herein is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water- miscible organic polymer, and an aqueous phase.
  • VPD co-solvent system is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM , and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • VPD co-solvent system is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM , and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of POLYSORBATE 80TM; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art.
  • Sustamed-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.
  • compositions suitable for use in the methods disclosed herein include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the exact formulation, route of administration and dosage for the pharmaceutical compositions disclosed herein can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al.
  • the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight, or 1 to 500 mg/kg, or 10 to 500 mg/kg, or 50 to 100 mg/kg of the patient's body weight.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. Note that for almost all of the specific compounds mentioned in the present disclosure, human dosages for treatment of at least some condition have been established.
  • the methods disclosed herein will use those same dosages, or dosages that are between about 0.1% and 500%, or between about 25% and 250%), or between 50% and 100% of the established human dosage.
  • a suitable human dosage can be inferred from ED 5 Q or ID 5 o values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals. [0157] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 500 mg of each ingredient, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of each ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceutical compositions disclosed herein or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day.
  • the compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day.
  • the total daily dosage by oral administration of each ingredient will typically be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will typically be in the range 0.1 to 400 mg.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • compositions should be administered using a regimen, which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • the amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • the compositions may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • Such notice for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions comprising a compound disclosed herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Example 1 Receptor Selection and Amplification Technology Assay
  • R-SAT The functional receptor assay, Receptor Selection and Amplification Technology (R-SAT), was used to investigate the pharmacological properties of known and novel FPRLl agonists.
  • R-SAT is disclosed in U.S. Patent Nos. 5,707,798, 5,912,132, and 5,955,281, all of which are hereby incorporated herein by reference in their entirety, including any drawings.
  • NIH3T3 cells were grown in 96 well tissue culture plates to 70- 80%) confluence. Cells were transfected for 16-20 h with plasmid DNAs using Polyfect (Qiagen Inc.) as per manufacturer's protocols.
  • R-SATs were generally performed with 3 ng/well of receptor and 20 ng/well of ⁇ -galactosidase plasmid DNA. All receptor and G- protein constructs used were in the pSI-derived mammalian expression vector (Promega fric) as described previously.
  • the FPRLl receptor gene was amplified by PCR from genomic DNA using oligodeoxynucleotide primers based on the published sequence (GenBank Accession # M84562). For large-scale transfections, cells were transfected for 16-20 h, then trypsinized and frozen in DMSO. Frozen cells were later thawed, plated at ⁇ 10,000 cells per well of a 96 half-area well plate that contained drug.
  • pECso is the negative of the log(EC 5 o), where EC 50 is the calculated concentration in Molar that produces 50% maximal activation.
  • Efficacy is relative to the ligand WKYMVm.
  • Example 2 FPRLl Receptor Binding Assay
  • the ability of the compounds disclosed herein to bind to the FPRLl receptors can be readily determined in a receptor binding assay.
  • [0168] 1. Grow FPRLl receptor-transfected COS cells (or another transfected cell line that does not endogenously express the FPRLl receptors may be substituted) in a suitable growth medium in 24-well culture plates.
  • radiolabeled assay solutions by mixing 245 ⁇ l of 0.25 nM [ 125 I]WKYMVm working solution with 5 ⁇ l of the following (one per solution): 50 ⁇ M unlabeled WKYMVm working solution, 0.25 nM [ 125 I] WKYMVm working solution, HEPES buffer only, or 5 Ox test compound. [0170] 3. Aspirate medium from 24-well plates using a Pasteur pipet attached to a vacuum source. Do not wash cells. [0171] 4. Add 250 ⁇ l radiolabeled assay solution from step 2 to each assay well and incubate plates 60 min at room temperature ( ⁇ 22°C) on an orbital shaker at low speed. [0172] 5.
  • HL-60 cells transfected with FPRLl or a control receptor at a density 1-3 x 10 cells/ml are washed with phosphate-buffered saline.
  • Cells are loaded with 2 ⁇ M Fura-2 and analyzed with respect to the rise in intracellular calcium in the presence or absence of varying concentration of compound.
  • 3. The response is compared to that elicited by the application of the standard reference ligand WKYMVm when tested at lOOnM.
  • hitracellular free calcium concentrations are calculated using the formula: where K d for Fura-2 is 224 nM, F max is the fluorescence in the presence of 0.04% Triton-XlOO and F m i n is the fluorescence obtained after the addition of 5 mM EGTA in 30 mM Tris-HCl, pH7.4.
  • Example 4 Determination of of anti-inflammatory and analgesic properties of FPRLl specific compounds.
  • Baseline responses, for naive, male Sprague-Dawley rats (175 - 200 g; n 6 per group) to a noxious thermal stimulus were measured using the 52°C hot plate test were determined.
  • Animals were injected intraperitoneally with vehicle, ibuprofen (100 mg/kg) or various doses of FPRLl specific compounds of Fomula I, H or HI.
  • Acute inflammatory pain was created by injecting 0.10 ml of 2% ⁇ - carrageenan (type IV; isolated from two species of seaweed Gigartina aci vide and G.
  • SEQ ID NO:l is the DNA sequence encoding the FPRLl receptor.
  • SEQ ID NO:2, below is the polypeptide sequence for the FPRLl receptor.
  • SKQ ID NO:l 1 ggcacgagga acaacctatt tgcaaagttg gcgcaaacat tcctgcctga caggaccatg 61 gacacaggtt gtagagatag agatggctct ggctgtgcat tcagcagatt ctgtagatag 121 aattaatagg acttggatgg gattgtggtg agagaaagtg aaatgaaaga taagttctag 181 ttggaagtt ttaacaactg aatgtttaaa ctcaaataga cacaaaatat tggaagagtg 2 1 gcaggttgg gaggatgaga caatcaactg tttggttgag ccacgttagg tttgaaatgt 301 ctacgggat
  • SEQ ID NO: 2 METNFSTPLNEYEEVSYESAGYTVLRILPLWLGVTFVLGV GN GLVI VAGFRMTRTVTTICYLNIiA ADFSFTAT PFLIVS AMGEKWPFGWFLCKLIH IWDINLFGSVFLIGFIALDRCICVLHPV AQNHRTVSLAMKVIVGP ILALVLTLPV FLFLTTVTIPNGDTYCTFNFASWGGTPEERLKVAITMLTARGIIRFVIGFSLPMSIVA ICYGLIAAKIHKKGMIKSSRP RVLTAWASFFIC FPFQLVALLGTV LKEMIJFYGK YKIIDILVNPTSS AFFNSCLNPMLYVFVGQDFRERLIHSLPTSIERA SEDSAPTND TAANSASPPAETELQAM

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Abstract

L'invention concerne des composés qui activent de manière sélective le récepteur FPRL1. L'invention concerne également des procédés destinés à soulager des réactions inflammatoires par régulation d'étapes clés dans le commerce illicite de leucocytes et dans la prévention de dommages tissulaires induits par des neutrophiles par administration à un sujet d'une quantité efficace sur le plan thérapeutique des composés de cette invention. En outre, cette invention concerne des procédés de modulation ou de production d'une action agoniste spécifique du récepteur FPRL1 par administration d'une quantité efficace des composés susmentionnés.
PCT/US2004/036952 2003-11-07 2004-11-04 Utilisation d'un recepteur de lipoxine, fprl1, en tant qu'outil d'identification de composes efficaces dans le traitement de douleurs et d'inflammations WO2005047899A2 (fr)

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CA002544983A CA2544983A1 (fr) 2003-11-07 2004-11-04 Utilisation d'un recepteur de lipoxine, fprl1, en tant qu'outil d'identification de composes efficaces dans le traitement de douleurs et d'inflammations
AU2004290368A AU2004290368A1 (en) 2003-11-07 2004-11-04 Use of the lipoxin receptor, FPRL1, as a tool for identifying compounds effective in the treatment of pain and inflammation
BRPI0416272-2A BRPI0416272A (pt) 2003-11-07 2004-11-04 usos do receptor fprl1, e de compostos, uso profilático de compostos, métodos de triagem para um composto capaz de afetar uma ou mais atividades de um receptor fprl1, de tratamento ou prevenção de inflamação, de identificação de um composto de indução de vasodilatação, para antagonismo de uma resposta vasoconstrutiva a um sulfidopeptìdeo leucotrieno em um indivìduo, e para estimulação de proliferação celular em um indivìduo, e, composto
EP04810415A EP1692502A2 (fr) 2003-11-07 2004-11-04 Utilisation d'un recepteur de lipoxine, fprl1, en tant qu'outil d'identification de composes efficaces dans le traitement de douleurs et d'inflammations
JP2006539672A JP2007516434A (ja) 2003-11-07 2004-11-04 リポキシン受容体ｆｐｒｌ１の、疼痛および炎症の治療に有効な化合物を識別する手段としての使用

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US7198912B2 (en) 2001-09-07 2007-04-03 Bristol-Myers Squibb Company Polynucleotides encoding a human G-protein coupled receptor, HGPRBMY39
WO2009077954A1 (fr) * 2007-12-14 2009-06-25 Actelion Pharmaceuticals Ltd Dérivés d'aminopyrazole
WO2009077990A1 (fr) * 2007-12-18 2009-06-25 Actelion Pharmaceuticals Ltd Dérivés d'aminotriazole comme agonistes d'alx
WO2010134014A1 (fr) * 2009-05-18 2010-11-25 Actelion Pharmaceuticals Ltd Dérivés de spiro[2.4]heptane pontés utiles en tant qu'agonistes du récepteur de alx et/ou du récepteur fprl2
WO2012074785A1 (fr) * 2010-12-03 2012-06-07 Allergan, Inc. Compositions pharmaceutiques comprenant des dérivés de la 3,4-dihydro-isoquinoléin-2(1h)-yl-3-phénylurée présentant une activité d'agoniste ou d'antagoniste de l'analogue-1 du récepteur des peptides formylés (fprl-1)
WO2012109544A1 (fr) * 2011-02-11 2012-08-16 Allergan, Inc. Nouveaux dérivés de 1-(1-oxo-1,2,3,4-tétrahydroisoquinolin-7-yl)urée en tant que modulateurs du récepteur de type 1 de n-formyl peptide (fprl-1)
WO2013062947A1 (fr) 2011-10-26 2013-05-02 Allergan, Inc. Dérivés amides d'acides aminés substitués par une n-urée à titre de modulateurs des récepteurs de type 1 du peptide formyle (fprl-1)
EP2597160A1 (fr) 2011-11-23 2013-05-29 Universita' Degli Studi "G. d'Annunzio" Chieti-Pescara Outil de criblage pour la découverte de médicament anti-inflammatoire comportant le promoteur de gène FPR2/ALX
US8580831B2 (en) 2009-06-09 2013-11-12 Actelion Pharmaceuticals Ltd. Fluorinated aminotriazole derivatives
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WO2015019325A1 (fr) 2013-08-09 2015-02-12 Actelion Pharmaceuticals Ltd Dérivés de benzimidazolyl-méthylurée en tant qu'agonistes du récepteur alx
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