AU2004290368A1 - Use of the lipoxin receptor, FPRL1, as a tool for identifying compounds effective in the treatment of pain and inflammation - Google Patents

Use of the lipoxin receptor, FPRL1, as a tool for identifying compounds effective in the treatment of pain and inflammation Download PDF

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AU2004290368A1
AU2004290368A1 AU2004290368A AU2004290368A AU2004290368A1 AU 2004290368 A1 AU2004290368 A1 AU 2004290368A1 AU 2004290368 A AU2004290368 A AU 2004290368A AU 2004290368 A AU2004290368 A AU 2004290368A AU 2004290368 A1 AU2004290368 A1 AU 2004290368A1
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heteroaryl
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Luis Gardell
Magnus Gustafsson
Norman Nash
Roger Olsson
Audra L. Scully
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Acadia Pharmaceuticals Inc
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Description

WO 2005/047899 PCTIUS2004/036952 "USE OF'THE!IIPOXINICEPTOR, FPRL1, AS A TOOL FOR IDENTIFYING COMPOUNDS EFFECTIVE IN THE TREATMENT OF PAIN AND INFLAMMATION Field of the Invention [0001] Aspects of the invention described below relate to the use of the Lipoxin Receptor, FPRL1, as a tool for identifying compounds effective in the treatment of pain and inflammation. This tool may be utilized in compound screening, but is not limited to this application of use. Specifically, 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. Additionally, compounds identified to be active at this receptor would be effective therapeutics administered prior to an inflammatory insult that would result in the activation of neutrophils, leading to: vasoconstrictive, inflammatory, myeloid suppressive, cardiovascular, and gastrointestinal diseases and subsequent pain associated with these conditions. Background of the Invention [0002] The immune response in human is a complex cascade of events that can be triggered by both endogenous and exogenous stimuli and once triggered, if gone unchecked, can result in significant tissue damage and eventual death. A diverse range of endogenous mediators are involved in this response, with key roles being played by eicosanoids such as prostaglandins and leukotrienes. These molecules exert their actions through activation of receptors on various leukocyte populations including neutrophils. 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 FPRL1, 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. - 1- WO 2005/047899 PCTIUS2004/036952 f0004] FPRL1 was first identified by Murphy et al. as a structurally related homologue of the N-formyl peptide receptor (FPR). This peptide, when released by bacteria during infection, has been shown to mediate chemotaxis and degranulation. Additionally, the hexapeptide WKYMVM has been shown to act as an agonist of the FPRL1 receptor in vitro in experiments looking at chemotaxis as well as in vitro assays designed to measure calcium mobilization. [0005] To date, no evidence has been provided to definitively support the role of the FPRL1 receptor in vivo in inflammation. Demonstrated here, with compounds selective for the FPRL1 receptor and active in vivo, is the link between the FPRL1 receptor and the alleviation of pain and inflammation; thus highlighting the importance of the FPRL1 receptor as a therapeutic target for drug discovery efforts in this field of medical need. Most of the eicosanoids derived from the metabolism of arachidonic acid have been demonstrated to exacerbate pain and inflammation in such diseases as asthma, glomerulonephritis, rheumatoid arthritis and Alzheimer's disease. In contrast, the selective FPRL1 compounds described here have been shown to prophylactically act as alleviators of inflammation and thus prove that the FPRL1 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] In a first embodiment, the invention includes the use of the FPRLl receptor as a tool to identify compounds effective in treating inflammation and associated pain. [0007] In a second embodiment, the invention includes the use of the FPRL1 resceptor as a screening tool to identify compounds effective in treating inflammation and associated pain. [0008] In a third embodiment, the invention includes the use of compounds specifically active at the FPRL1 receptor as therapeutics for treating inflammation and associated pain. [0009] In a fourth embodiment, the invention includes the prophylactic use of compounds specifically active at the FPRL1 receptor as therapeutics for blocking inflammation and associated pain. -2- WO 2005/047899 PCTIUS2004/036952 [U0101 In a fifth embodiment, the invention includes a method of screening for a compound able to affect one or more activities of a FPRL1 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 FPRL1 receptor, provided that said cell does not have functional FPRL1 receptor expression from endogenous nucleic acid, and b) determining the ability of said test compound to affect one or more activities of said FPRL1 receptor, and comparing said ability with the ability of said test compound to affect said one or more FPRL1 receptor activities in a cell not comprising said recombinant nucleic acid; wherein said recombinant nucleic acid comprises a FPRL1 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) a derivative of either nucleic acid molecule in i) or ii), wherein said derivative encodes a receptor having one or more activities of said FPRL1 receptor and comprises at least 20 contiguous nucleotides which can hybridize under stringent hybridization conditions to the compliment of the nucleic acid of SEQ ID NO:1. [0011] In one aspect of the fifth embodiment, said FPRL1 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. [00121 In a sixth embodiment, 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, II, or III, wherein the compound activates a FPRL1 receptor subtype. In 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 -.3 - WO 2005/047899 PCTIUS2004/036952 syndrome, 'Criohn'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, systemic lupus erythematosus, chronic renal disease, cardiovascular disease, and hypertension or chemical injury. [00131 In a seventh embodiment, the invention includes a method of identifying a compound which is an agonist of the FPRL1 receptor, the method comprising: contacting a FPRL1 receptor with at least one test compound of Formula I, II, or III; and determining any increase in activity level of said FPRL1 receptor so as to identify a test compound which is an agonist of the FPRL1 receptor. [00141 In an eighth embodiment, the invention includes a method of identifying a compound which is an agonist of a FPRL1 receptor, the method comprising: culturing cells that express said FPRL1 receptor; incubating the cells or a component extracted from the cells with at least one test compound of Formula I, II, or III; and determining any increase in activity of said FPRL1 receptor so as to identify a test compound which is an agonist of a FPRL1 receptor. [0015] In one aspect of the eighth embodiment, the cultured cells overexpress said FPRL1 receptor. In another aspect of the eighth embodiment, the identified agonist is selective for the FPRLl receptor. [00161 In a ninth embodiment 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. [0017] In one aspect of the ninth embodiment, the method further comprises the step of identifying an individual in need of inflammatory treatment prior to the contacting step. In another aspect of the ninth embodiment, said compound of Formula I, II, or III selectively activates the FPRL1 receptor subtype. In a further aspect of the ninth embodiment, 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. In still another aspect of the ninth embodiment, the -4- WO 2005/047899 PCT/US2004/036952 fifflammatory response is associated with rheumatoid arthritis, Azheimer's disease or asthma. In another aspect of the ninth embodiment, the inflammatory response results from physical injury, including physical trauma and radiation exposure. [00181 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, II, or IIL [00191 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 III. In one aspect of the eleventh embodiment, 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. [00201 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, II, or II. In one aspect of the twelfth embodiment, 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 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. In another aspect of the twelfth embodiment, 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. [0021] 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, II, or II. -5- WO 2005/047899 PCTIUS2004/036952 [00221 A fourteenth embodiment of the invention includes a compound of Formula I H N-N
R
4
R
3 R6d N R 2
R
5 or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein
R
1 is selected from the group consisting of C1-C 10 straight chained or branched alkylene, oxygen, sulfur, NQ, CHCN, C=0, C=S, C=NQ, S=0, S(=0) 2 , C=NOQ, wherein Q is independently selected from the group consisting of hydrogen, C 1 -C10 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C 2 -Cio straight chained or branched alkenyl optionally substituted with an aryl or heteroaryl, C 2
-C
10 straight chained or branched alkynyl optionally substituted with an aryl or heteroaryl, C 3 CIO cycloalkyl, and C5-C10 cycloalkeny1; each of R 2 , R 3 , R 4 , and R 5 is independently selected from the group consisting of hydrogen, C 1
-C
10 straight chained or branched alkyl, C 2
-C
10 straight chained or branched alkenyl, C 2 -Cio straight chained or branched alkynyl, C 3 -Cio cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, -OR 7 , -N(R 7
)
2 , -CN, -C(=Z)R 7 , -C(=Z)OR 7 ,
-C(=Z)N(R
7
)
2 , -N(R7)-C(=Z)R 7 , -N(R 7
)-C(=Z)N(R)
2 ,
-OC(=Z)R
7 , and -SR 7 , wherein Z is oxygen or sulfur; and wherein each R 7 is independently selected from the group consisting of hydrogen, C 1 -Cio straight chained or branched alkyl optionally substituted with an aryl or heteroaryl,
C
2
-C
10 straight chained or branched alkenyl optionally substituted with an aryl or heteroaryl, C 2 Cio straight chained or branched alkynyl optionally -6- WO 2005/047899 PCT/US2004/036952 substituted with an aryl or heteroaryl, C 3
-C
10 cycloalkyl, and C 5
-C
10 cycloalkenyl; or
R
3 and R 4 and the nitrogen to which they are attached form a fused heteroaryl, or heterocyclic ring.
R
6 may be present 0-5 times and is independently selected from the group consisting of hydrogen, C 1
-C
4 straight chained or branched alkyl, cycloalkyl, aryl or heteroaryl optionally substituted, hydroxy, nitro, amino, halogen, sulphonate, perhaloalkyl, -OR 7 , -N(Rs) 2 , -CN, -C(=Z)Rg, -C(=Z)OR 8 ,
-C(=Z)N(R)
2 , -N(RS)-C(=Z)R 8 , -N(R 8
)-C(=Z)N(RS)
2 , -OC(=Z)R8, and SRs, wherein Z is oxygen or sulfur; and wherein each RS is independently selected from the group consisting of hydrogen, C-C 10 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C 2
-C
1 O 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 10 cycloalkyl, and C 5
-C
10 cycloalkenyl; or
"R
6 " form a fused aryl or heteroaryl ring [00231 In one aspect of the fourteenth embodiment, R 1 is hydrogen or C-C 10 straight chained alkyl. In another aspect of the fourteenth embodiment, R 1 is C-Cs straight chained alkylene. In yet another aspect of the fourteenth embodiment, R 1 is selected from the group consisting of methylene, ethylene, n-propylene, isopropylene, n-butylene, sec butylene, tert-butylene, n-pentylene, and isopentylene. In still another aspect of the fourteenth embodiment, R 2 is selected from the group consisting of hydrogen, hydroxy, nitro, amino, aryl, heteroaryl, -OR 7 , and -N(R 7
)
2 , and wherein R 7 is hydrogen or C-Cio straight chained allyl. For example, in the preceding aspect, R 7 may be hydrogen or Cr-C 3 straight chained alkyl. In a further aspect of the fourteenth embodiment, R 2 is selected from the group consisting of hydrogen, hydroxy, nitro, aryl, heteroaryl, methoxy, and ethoxy. In another aspect of the fourteenth embodiment, 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-Cio straight chained alkyl. In still a further aspect of the fourteenth embodiment, R 7 is hydrogen or Cr-C 3 straight chained alkyl. In another aspect of the -7- WO 2005/047899 PCTIUS2004/036952 tourteeifli embodiment, F,3 is selected from the group consisting of hydrogen, nitro, aryl, heteroaryl. In a further aspect of the fourteenth embodiment, wherein R 4 is selected from the group consisting of hydrogen, CI-C 10 straight chained alkyl, hydroxy, nitro, amino, halogen, -OR 7 , and -N(R 7
)
2 , and wherein R 7 is C-Cio straight chained or branched alkyl optionally substituted with an aryl or heteroaryl. In a further aspect of the fourteenth embodiment, R 4 is selected from the group consisting of hydrogen, C-C 3 straight chained alkyl, hydroxy, nitro, amino, halogen, -OR 7 , and -N(R 7
)
2 , and R 7 is C-C 3 straight chained alkyl optionally substituted with an aryl. In yet another aspect of the fourteenth embodiment, R 4 is selected from the group consisting of hydrogen, methyl, ethyl, hydroxy, nitro, amino, chloro, fluoro, methoxy, ethoxy, methylamino, dimethylamino, diethylamino, and benzyloxy. In still a further aspect of the fourteenth embodiment, R 5 is selected from the group consisting of hydrogen, CI-Cio straight chained alkyl, hydroxy, nitro, amino, halogen, perhaloalkyl, -OR 7 , and -N(R 7
)
2 , and wherein R 7 is C 1
-C
10 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl. In an additional aspect of the fourteenth embodiment, 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 7 is CI-C 3 straight chained alkyl. In another aspect of the fourteenth embodiment,
R
5 is selected from the group consisting of hydrogen, hydroxy, chloro, romo, trifluoromethyl, and methoxy. In some aspects of the fourteenth embodiment, R 6 is hydrogen. In another aspect of the fourteenth embodiment, R 2 and R 3 and the nitrogen to which they are attached form a fused heteroaryl or heterocyclic alkyl ring. For example, in the preceding aspect the ring may be a heterocyclic alkyl ring. In some instances, the heterocyclic alkyl ring may be selected from the group consisting of N-morpholine and pyrrole. [0024] A fifteenth embodiment of the present invention includes a compound selected from the group consisting of H N-N H H N-N _L H ~N I\ N -,,r N O/ N N 0 x -8 -8- WO 2005/047899 PCT/US2004/036952 H N-N H COOH H N-N 0 N /- _ N I1 O N N N N N N 0 0 H N-N H N-N H N/\ N N /\ Nb S- 0 I CI 00 H N-N H 0H N-N H N l- _ N\ N- " N-. N / \- N o N N S"), 0 C' l H N-N H N H, N-N H 9 H.- : N 0 H N-N0 NI ~H N-N N N N H N-N H NH N-N H N 0N I\ N ci'l ,and N -9- WO 2005/047899 PCT/US2004/036952 [0025] A sixteenth embodiment of the present invention includes a compound of Formula II HH
R
3 R O N N
X
1 N X2 R2 or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein each of X 1 and X 2 is independently oxygen or sulfur; R1 is selected from the group consisting of C 1 -Cio straight chained or branched alkylene, oxygen, sulfur, NQ, CHCN, C=O, C=S, C=NQ, S=O, S(=0) 2 , C=NOQ wherein Q is selected from the group consisting of hydrogen, C 1
-C
10 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C 2 -Cio 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
10 cycloalkyl, and C 5 -Co cycloalkenyl; each of R2, R3, is independently selected from the group consisting of hydrogen, CI-Cia straight chained or branched alkyl, C 2 -Cio straight chained or branched alkenyl, C 2 -Cio straight chained or branched alkynyl, C 3 -Cio cycloalcyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, -OR7, -N(R) 2 , -CN, -C(=Z)R7,-C(=Z)OR7,
-C(=Z)N(R
7
)
2 , -N(R 7
)-C(=Z)R
7 ,
-N(R
7
)-C(=Z)N(R
7
)
2 , -OC(=Z)R 7 , , and -SR 7 , wherein Z is oxygen or sulfur; and wherein each R 7 is independently selected from the group consisting of hydrogen, C 1
-C
10 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C 2
-C
1 o straight chained or branched alkenyl optionally substituted with an aryl or heteroaryl, C 2
-C
1 0 straight chained or -10- WO 2005/047899 PCT/US2004/036952 branched alkynyl optionally substituted with an aryl or heteroaryl, C 3
-C
1 0 cycloalkyl, and C 5
-C
10 cycloalkenyl. [0026] In one aspect of the sixteenth embodiment, R 1 is selected from the group consisting of oxygen and NQ, wherein Q is selected from the group consisting of hydrogen,
CI-C
5 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl. For example, in some versions of the preceding aspect of the sixteenth embodiment, Q is
CI-C
3 straight chained or branched alkyl. In other versions of the preceding aspect of the sixteenth embodiment, Q is selected from the group consisting of methyl, ethyl, and propyl. In further versions of the preceding aspect of the sixteenth embodiment, Q is methyl. In another aspect of the sixteenth embodiment, R 2 is selected from the group consisting of hydrogen, C-Cio straight chained or branched alkyl, C 3
-C
10 cycloalkyl, and optionally substituted aryl. For example, in one version of the preceding aspect, R 2 is substituted aryl. In another version of the preceding aspect, R 2 is selected from the group consisting of 4-alkylphenyl, 4-alkoxyphenyl, 4-alkoxycarbonylphenyl. In another version of the preceding aspect, R 2 is selected from the group consisting of 4-methylpheynl, 4 ethoxyphenyl, and 4-ethoxycarbonylphenyl. In another aspect of the sixteenth embodiment, R3 is selected from the group consisting of hydrogen, C-C 10 straight chained or branched alkyl, C 3
-C
10 cycloalkyl, and optionally substituted aryl. For example, in one version of the preceding aspect, R 3 is substituted aryl. In another version of the preceding aspect, R 3 is selected from the group consisting of 4-alkylphenyl, 4-alkoxyphenyl, and 4-halophenyl. For example, in some instances, R3 may be selected from the group consisting of 4 chlorophenyl, 4-bromophenyl, and 4-methoxyphenyl. [0027] A seventeenth embodiment of the present invention includes a compound of Formula III 6 R 1 ( I N R 4
R
2 R 3 or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein each of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from the group consisting of hydrogen, C-Cio straight chained or branched alkyl,
C
2
-C
10 straight chained or branched alkenyl, C 2
-C
10 straight chained - 11 - WO 2005/047899 PCT/US2004/036952 or branched alkynyl, C 3
-C
10 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, -OR 7 , -N(R 7
)
2 , -CN,
-C(=Z)R
7 ,-C(=Z)OR7, -C(=Z)N(R 7
)
2 , -N(R7)-C(=Z)R7, -N(R7)-C(=Z)N(R 7
)
2 , -OC(=Z)R 7 ,, and -SR 7 wherein Z is oxygen or sulfur; and wherein each R 7 is independently selected from the group consisting of C-Cio straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C 2
-C
10 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
10 cycloalkyl, and
C
5 -Cio cycloalkenyl; or
R
3 and R 4 and the nitrogen to which they are attached form a fused heteroaryl, or heterocyclic ring;
R
5 and R 6 and the nitrogen to which they are attached form a fused heteroaryl, or heterocyclic ring; or
R
1 , R 2 , the carbon to which R 1 is attached, and the nitrogen to which R 2 is attached form a fused heteroaryl, or heterocyclic ring. [0028] In one aspect of the seventeenth embodiment, R 1 is selected from the group consisting of hydrogen and optionally substituted C 1
-C
10 straight chained or branched alkyl. In one version of the preceding aspect of the seventeenth embodiment, R 1 is Ci-C 5 straight chained alkyl optionally substituted with an aryl or heteroaryl ring. For example, in some instances said aryl ring is phenyl. In other instances, said heteroaryl ring comprises nitrogen. In some instances said heteroaryl ring is indole. In a further aspect of the seventeenth embodiment, R 1 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 R 1 is selected from the group consisting of methyl, indolylmethyl, benzyl, and sec-butyl. In another aspect of the seventeenth embodiment, R 1 , R 2 , the carbon to which R 1 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. In a further aspect of the seventeenth embodiment, R 2 , R 3 , and R 5 are each - 12 - WO 2005/047899 PCT/US2004/036952 inctependently selected from the group consisting of hydrogen, C 1
-C
4 straight chained or branched alkyl, C 2 -Cs straight chained or branched alkenyl, and C 2
-C
5 straight chained or branched alkynyl. In some versions of the preceding aspect, said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, see-butyl, and tert-butyl. In other versions of the preceding aspect, R 2 , R 3 , and R 5 are hydrogen. In another aspect of the seventeenth embodiment, R 4 is optionally substituted aryl. For example, in some versions of the preceding aspect, said aryl is phenyl. In other versions of the preceding aspect, said aryl is optionally substituted with halo, alkoxy, alkyl, alkylthio, and perhaloalkyl. In some versions of the preceding aspect , said aryl is optionally substituted with chloro, bromo, methyl, ethyl, isopropyl, methoxy, methylthio, and trifluormethyl. In other versions of the preceding aspect, 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. In another aspect of the seventeenth embodiment, R 6 is selected from the group consisting of optionally substituted C 1 -Cia straight chained or branched alkyl, and optionally substituted heterocyclic ring. In some versions of the preceding aspect, said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert butyl, pentyl, and 1-methylbutyl. For example, in some instances, said alkyl is substituted with a heterocyclic ring or a substituted amine. In some instances, said heterocyclic ring is morpholine. In other instances, said heterocyclic ring is piperidine or morpholine. In another aspect of the seventeenth embodiment, R 6 is selected from the group consisting of 1-methyl-4-diethylaminobutyl, 2-N-morpholinoethyl, and N-benzylpiperidin-4-yl. In a further aspect of the seventeenth embodiment, 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. In some versions of the preceding aspect, said heterocyclic ring is piperidine or benzopiperidine. In a further aspect of the seventeenth embodiment, R 5 and
R
6 and the nitrogen to which they are attached form a substituent selected from the group consisting of 0 0 0 ND N 5--N , and [0029] An eighteenth embodiment of the present invention includes a compound selected from the group consisting of - 13 - WO 2005/047899 PCT/US2004/036952 H N-N H NN H N-N H 0 a 0 NN HO ) N HONN Br NH N CI NH 0 N N N N N O N>~ 0 NS 00 0 1"0 N 0 Br N N H H HN HN 0HN HN 0 0 N 1 N N 'kN ,and H H [0030] In a certain embodiment the FPRL1 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 FPRL1 receptor by comparing the response elicited by FPRL1 transfected cells with those devoid of the FPRL1 -14- WO 2005/047899 PCT/US2004/036952 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 FPRL1 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 determined to be an agonist, antagonist or inverse agonist of the FPRLl receptor. [00311 In certain embodiments, disclosed herein is a method of identifying a compound which is an agonist of a FPRL1 receptor, the method comprising culturing cells that express the FPRLl receptor; incubating the cells with at least one compound and determining any increase in activity of the FPRL1 receptor so as to identify a compound of which is an agonist of a FPRL1 receptor. [0032] In certain embodiments, the cultured cells overexpress said FPRL1 receptor. In other embodiments, the identified agonist is selective for the FPRL1 receptor. In another aspect, the invention relates to a method of identifying a mutation in the FPRL1 receptor gene, the mutation being suspected of conferring constitutive activity on the receptor, the method comprising: (a) extracting nucleic acid from a biological sample obtained from an individual having a disorder or condition putatively associated with constitutive activity of the FPRLI receptor; (b) preparing cDNA from the extracted nucleic acid; (c) selecting from the cDNA in step (b) cDNA encoding the FPRL1 receptor; (d) transfecting a cell with an expression vector comprising said selected cDNA; (e) selecting a cell expressing constitutively active FPRL1 receptor; and (f) sequencing the cDNA in said selected cell to detect the mutation(s). [0033] In a further aspect, 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: (a) obtaining a biological sample from an individual putatively affected by or susceptible to a disorder or condition associated with constitutive activity of the FPRL1 receptor; (b) isolating from said biological sample a nucleic acid sequence encoding said receptor, or a portion of said nucleic acid sequence corresponding to the portion of the gene identified to include mutation(s) by the mutation identification method described above; and (c) detecting the presence or absence of the mutation(s) in said nucleic acid sequence or said portion thereof. - 15 - WO 2005/047899 PCT/US2004/036952 [0034] The presence of one or more mutations in the nucleic acid sequence may, for example, be detected by sequencing the nucleic acid sequence and comparing it with a sequence known or previously identified to contain mutation(s). [0035] In another aspect, the present invention relates to a test kit for detecting mutation(s) in the gene encoding the FPRL1 receptor, said mutations giving rise to constitutive activity of the FPRL1 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. [0036] In certain embodiments, disclosed herein is a method of identifying a compound which is an agonist of a FPRL1 receptor, the method comprising culturing cells that express the FPRL1 receptor; incubating the cells with at least one compound and determining any increase in activity of the FPRL1 receptor so as to identify a compound of which is an agonist of a FPRL1 receptor. [0037] In certain embodiments, the cultured cells overexpress said FPRL1 receptor. In other embodiments, the identified agonist is selective for the FPRL1 receptor. [00381 In certain embodiments, disclosed herein is a method of identifying a compound which is an antagonist or inverse agonist of a FPRL1 receptor, the method comprising culturing cells that express the FPRL1 receptor; incubating the cells with at least one compound and determining any decrease in activity of the FPRL1 receptor so as to identify a compound of which is an agonist of a FPRL1 receptor. [0039] In certain embodiments, the cultured cells overexpress said FPRL1 receptor. In other embodiments, the identified antagonist or inverse agonist is selective for the FPRL1 receptor. [0040] It will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure. [00411 Further disclosed herein are compounds of Formula I, Formula II, or Formula III -16- WO 2005/047899 PCT/US2004/036952 H1 3 R1 HN 0 NJ H N-N R 4
R
3 N R N I \ S R(N R 2 X1 N~ ~ ~ 0, N -X (Ri R 6 R6 R5 1 N 0 N0 I I R
R
2
R
3 as defined herein, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, that selectively activate the FPRL1 receptor. Further disclosed are methods of alleviating inflammatory responses by regulating key steps in leukocyte trafficking and preventing neutrophil-mediated tissue damage by administering to a subject a therapeutically effective amount of a compound of Formula I, Formula II, or Formula III. In addition, methods of modulating, or specifically agonizing, the FPRLI receptor administering an effective amount of a compound of Formula I, Formula II, or Formula III are also disclosed. [0042] Other embodiments of the present invention are disclosed below. Brief Description of the Drawings [0043] Figure 1 illustrates effects of varying dosages of Compound 7 on thermal hyperalgesia at various time points. [0044] Figure 2 illustrates effects of varying dosages of Compound 7 on thermal hyperalgesia. [0045] Figure 3 illustrates the %hyperalgesia observed at varying dosages of Compound 7. [0046] Figure 4 illustrates the effects of varying dosages of Compound 7 on edema formation. Detailed Description of the Preferred Embodiment [0047] In a first aspect, disclosed herein is a compound of Formula I H N-N
R
4
R
3 N /\ 2 R__ NN
R(NR
2
R
6 ~ R R5 or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, - 17 - WO 2005/047899 PCT/US2004/036952 wherein
R
1 is selected from the group consisting of C 1
-C
10 straight chained or branched alkylene, oxygen, sulfur, NQ, CHCN, C=O, C=S, C=NQ, S=O, S(=0) 2 , C=NOQ, wherein Q is independently selected from the group consisting of hydrogen, C 1
-C
10 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C 2
-C
1 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 -CIO cycloalkyl, and C 5 -Cio cycloalkenyl; each of R 2 , R 3 , R 4 , and R 5 and is independently selected from the group consisting of hydrogen, C 1
-C
10 straight chained or branched alkyl,
C
2 -Cio straight chained or branched alkenyl, C 2
-C
1 O straight chained or branched alkynyl, C 3
-C
10 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, -OR 7 , -N(R 7
)
2 , -CN,
-C(=Z)R
7 , -C(=Z)OR 7 , -C(=Z)N(R 7
)
2 , -N(R 7
)-C(=Z)R
7 , -N(R7)-C(=Z)N(R 7
)
2 , -OC(=Z)R 7 , and -SR7, wherein Z is oxygen or sulfur; and wherein each R 7 is independently selected from the group consisting of hydrogen, CI-C 10 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C 2 -Cio 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-Cio cycloalkyl, and C 5 -Cio cycloalkenyl; or
R
3 and R 4 and the nitrogen to which they are attached form a fused heteroaryl, or heterocyclic ring.
R
6 may be present 0-5 times and is independently selected from the group consisting of hydrogen, C 1
-C
4 straight chained or branched alkyl, cycloalkyl, aryl or heteroaryl optionally substituted, hydroxy, nitro, amino, halogen, sulphonate, perhaloalkyl, -OR 7 , -N(Rs) 2 , -CN, -C(=Z)Rs, -C(=Z)OR 8 , -18- WO 2005/047899 PCTIUS2004/036952 -C(=Z)N(Rs) 2 , -N(R 8
)-C(=Z)R
8 , -N(Rs)-C(=Z)N(R) 2 , -OC(=Z)Rs, and SR 8 , wherein Z is oxygen or sulfur; and wherein each R 8 is independently selected from the group consisting of hydrogen, C 1
-C
10 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C 2
-C
10 straight chained or branched alkenyl optionally substituted with an aryl or heteroaryl, C 2
-C
10 straight chained or branched alkynyl optionally substituted with an aryl or heteroaryl, C 3
-C
10 cycloalkyl, and C 5
-C
10 cycloalkenyl; or
"R
6 " form a fused aryl or heteroaryl ring. [0048] In certain embodiments, R 1 in the compound of Formula I is C 1
-C
10 straight chained alkylene. In some embodiments, R 1 is C 1
-C
5 straight chained alkylene. In further embodiments, R 1 is selected from the group consisting of methylene, ethylene, n propylene, isopropylene, n-butylene, sec-butylene, tert-butylene, n-pentylene, and isopentylene. [0049] In some embodiments, R 2 in the compound of Formula I is selected from the group consisting of hydrogen, hydroxy, nitro, amino, halogen, -OR 7 , and -N(R 7
)
2 , and wherein R 7 is hydrogen, aiyl, heteroaryl or C 1
-C
10 straight chained alkyl. In certain embodiments, R 2 is selected from the group consisting of hydrogen, hydroxy, nitro, halogen, and -OR 7 , and wherein R 7 is hydrogen or C 1
-C
3 straight chained alkyl. In other embodiments, R 2 is selected from the group consisting of hydrogen, hydroxy, nitro, methoxy, and ethoxy. [00501 In certain embodiments, R 3 in the compound of Formula I is selected from the group consisting of hydrogen, hydroxy, nitro, amino, halogen, -OR 7 , and -N(R 7
)
2 , and wherein R 7 is hydrogen, aryl, heteroaryl or C 1 -Cio straight chained alkyl. In some embodiments, R 3 is selected from the group consisting of hydrogen, hydroxy, nitro, and OR 7 , and wherein R 7 is hydrogen or C 1
-C
3 straight chained alkyl. In other embodiments,
R
3 is selected from the group consisting of hydrogen, nitro, hydroxy, methoxy and ethoxy. [00511 Embodiments include those in which R 4 in the compound of Formula I is selected from the group consisting of hydrogen, C 1 -C1O straight chained alkyl, hydroxy, nitro, amino, halogen, -OR 7 , and -N(R 7
)
2 , and wherein each R 7 is independently C 1 -Cio straight chained or branched alkyl optionally substituted with an aryl or heteroaryl. In some - 19 - WO 2005/047899 PCTIUS2004/036952 embodiments, R 4 is selected from the group consisting of hydrogen, Ci-C 3 straight chained alkyl, hydroxy, nitro, amino, halogen, -OR 7 , and -N(R 7
)
2 , and wherein each R 7 is independently C 1
-C
3 straight chained alkyl optionally substituted with an aryl. In yet other embodiments, R 4 is selected from the group consisting of hydrogen, methyl, ethyl, hydroxy, nitro, amino, chloro, fluoro, methoxy, ethoxy, methylamino, dimethylamino, diethylamino, and benzyloxy. [0052] In further embodiments, R 5 in the compound of Formula I is selected from the group consisting of hydrogen, aryl, heteroaryl, C 1 -Cio straight chained alkyl, hydroxy, nitro, amino, halogen, perhaloalkyl, -OR 7 , and -N(R 7
)
2 , and wherein each R 7 is independently C 1
-C
10 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl. In other embodiments, R 5 is selected from the group consisting of hydrogen,
C
1
-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 1
-C
3 straight chained alkyl. In certain embodiments, R 5 is selected from the group consisting of hydrogen, hydroxy, chloro, bromo, trifluoromethyl, and methoxy. 10053] In some embodiments R 6 is hydrogen. [0054] As mentioned above, in some embodiments R 2 and R 3 and the nitrogen to which they are attached form a fused heteroaryl or heterocyclic alkyl ring. In some embodiments, the ring is a fused heterocyclic alkyl ring, which may be a N-morpholine or pyrrole. [00551 In certain embodiments, the compound of Formula I is selected from the group consisting of H N-N H H N-N H N N 1- 'N s jJjN6 " N S 0 O0 00 H N-N H COOH H N-N O N N N N N N 0 Cl -20- WO 2005/047899 PCT/US2004/036952 H N-N H N-N H O N N N N _6 0 0 H N-N H H N-N H N O\ N N I N HN N S H N N N ,Q H N--, N H 0 0 0 ON HO N H N-N H N / N N H N-N H 0 N O 'N HO 011 H N-N H ON N NN NN C' H N-N H NO N N S N ' H N-N H N N I\N 00 'N N-S X0X2 ,and 'N [0056] hIn another aspect, disclosed herein is a compound of Formula 1I
R
3 R HN N (II) N R2 or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein -21- WO 2005/047899 PCT/US2004/036952 each of X 1 and X 2 is independently oxygen or sulfur;
R
1 is selected from the group consisting of C 1
-C
10 straight chained or branched alkylene, oxygen, sulfur, NQ, CHCN, C=0, C=S, C=NQ, S=O, S(=0) 2 , C=NOQ wherein Q is selected from the group consisting of hydrogen, C 1
-C
1 0 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C 2
-C
10 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 -Cio cycloalkyl, and C 5
-C
10 cycloalkenyl; each of R 2 , R 3 , is independently selected from the group consisting of hydrogen, C 1
-C
10 straight chained or branched alkyl, C 2
-C
10 straight chained or branched alkenyl, C 2
-C
1 O straight chained or branched alkynyl, C 3 Cio cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, -OR 7 , -N(R 7
)
2 , -CN,
-C(=Z)R
7
,-C(=Z)OR
7 , -C(=Z)N(R 7
)
2 , -N(R 7
)-C(=Z)R
7 ,
-N(R
7
)-C(=Z)N(R
7
)
2 , -OC(=Z)R 7 , , and -SR 7 , wherein Z is oxygen or sulfur; and wherein each R 7 is independently selected from the group consisting of hydrogen, C 1
-C
10 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C 2
-C
10 straight chained or branched alkenyl optionally substituted with an aryl or heteroaryl, C 2
-C
10 straight chained or branched alkynyl optionally substituted with an aryl or heteroaryl, C 3
-C
1 0 cycloalkyl, and C 5
-C
10 cycloalkenyl. [00571 In certain embodiments, the compound of Formula II is selected from the group consisting of - 22 - WO 2005/047899 PCTIUS2004/036952 N / /-N/ Br NH Cl NH 0 N N N 0 N S 0 1cC 0 0 Br / NH Br / NH N -0 NJ N 0 N N 0 N S 0 0 ,and 0 0 NH N N N O 0 N>~ 0 0 [0058] In yet another aspect, disclosed herein is a compound of Formula iII
R
6 R5"l RNX 00 R, NkNR4
R
2
R
3 or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein - 23 - WO 2005/047899 PCT/US2004/036952 each of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from the group consisting of hydrogen, CI-C 10 straight chained or branched alkyl,
C
2
-C
10 straight chained or branched alkenyl, C 2
-C
10 straight chained or branched alkynyl, C 3 -Cio cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, -OR 7 , -N(R 7
)
2 , -CN,
-C(=Z)R
7
,-C(=Z)OR
7 , -C(=Z)N(R 7
)
2 , -N(R7)-C(=Z)R7,
-N(R
7
)-C(=Z)N(R
7
)
2 , -OC(=Z)R 7 ,, and -SR 7 wherein Z is oxygen or sulfur; and wherein each R 7 is independently selected from the group consisting of C 1
-C
10 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C 2 -Cio 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 -Cio cycloalkyl, and
C
5
-C
10 cycloalkenyl; or
R
3 and R 4 and the nitrogen to which they are attached form a fused, heteroaryl, or heterocyclic ring;
R
5 and R 6 and the nitrogen to which they are attached form a fused heteroaryl, or heterocyclic ring; or
R
1 , R 2 , the carbon to which R 1 is attached, and the nitrogen to which R 2 is attached form a fused heteroaryl, or heterocyclic ring. [00591 In certain embodiments, R 1 of the compound of Formula III is selected from the group consisting of hydrogen and optionally substituted C 1
-C
10 straight chained or branched alkyl. In other embodiments, R 1 may be C-C 5 straight chained alkyl optionally substituted with an aryl or heteroaryl ring. In some embodiments, 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. In some embodiments, the alkyl group of R 1 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. In certain embodiments, R 1 is selected from the group consisting of methyl, indolylmethyl, benzyl, and sec-butyl. - 24 - WO 2005/047899 PCT/US2004/036952 [0060] In some embodiments, R 1 , R 2 , the carbon to which R 1 is attached, and the nitrogen to which R 2 is attached form a fused heteroaryl, or heterocyclic ring. The heterocyclic ring may be pyrolidine. [0061] In certain embodiments, R 2 , R 3 , and R 5 of the compound of Formula III are each independently selected from the group consisting of hydrogen, C-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. In some embodiments, the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. In further embodiments, R 2 , R 3 , and R 5 are hydrogen. [0062] Tn some embodiments, R 4 of the compound of Formula III is an optionally substituted aryl. In certain embodiments, the aryl is phenyl. In some of these embodiments, the aryl is optionally substituted with halo, alkoxy, alkyl, alkylthio, and perhaloalkyl. In further embodiments, the aryl is optionally substituted with chloro, bromo, methyl, ethyl, isopropyl, methoxy, methylthio, and trifluonnethyl. In some embodiments,
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. [00631 Embodiments of the present disclosure include those in which R 6 of the compound of Formula III is selected from the group consisting of optionally substituted C
C
10 straight chained or branched alkyl, and optionally substituted heterocyclic ring. 'In some embodiments, the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, and 1-methylbutyl. In further embodiments, the alkyl is substituted with a heterocyclic ring or a substituted amine. In some embodiments the heterocyclic ring with which the alkyl is substituted is morpholine. In certain embodiments, R 6 is an optionally substituted heterocyclic ring, which may be piperidine or morpholine. In further embodiments, R 6 is selected from the group consisting of 1 -methyl-4-diethylaminobutyl, 2-N-morpholinoethyl, and N-benzylpiperidin-4-yl. [00641 In some embodiments, R 5 and R 6 of the compound of Formula III and the nitrogen to which they are attached form an optionally substituted fused heteroaryl, or an optionally substituted heterocyclic ring. In certain embodiments, the heterocyclic ring is piperidine or benzopiperidine. In other embodiments, R 5 and R 6 and the nitrogen to which they are attached form a substituent selected from the group consisting of - 25 - WO 2005/047899 PCTIUS2004/036952 0 0 0 o -N1 '-N ,and -N [0065] In certain embodiments, the compound of Formula III is selected from the group consisting of N Cl N N H H N 0 Br H N H N 0 0H N N 0 0 X N Nf~ N ~Na H H H H -26 WO 2005/047899 PCTIUS2004/036952 N N H N HN 0S HN HN 00 CF 3 N I NN N N N B H H H H -0 0- 0 HN NO 0 HN HN 0 Br N N N O N H H H H 0 0 0 0 HN N 0 0 1HN N 0 0 S, N NC N ) N H H H H N 0 CI N 0 IN 0 Br 0 70 70 7 N N N NJO N N H H H H H H N 0 0 CI c N N ( N NO H H 0 N N H - 27 - WO 2005/047899 PCTIUS2004/036952 NN NN NOB N 0 N O r 0 N N C N N B H H O S N N 00 O N 00 f cI . N N N N~ H H H H ' N ( ' - -N N 0 0 l-N 0 0 N NJ:) H H H H O 0 H HN N 0 0CI HN N 0 0Br Na JN Na H H H H 0~ ,-IN 0 , CI N N J H H - 28 - WO 2005/047899 PCT/US2004/036952 N0 HN 0 O Br N N N 0 Br H H O N N H 0 N N N N H U Hx F0 -O N N 0 ~ 0 N 0 0CI N O Osf H H N CN ,and H H [0066] The term "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. - 29 - WO 2005/047899 PCT/US2004/036952 100671 The term "ester" 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. [0068] An "amide" is a chemical moiety with formula -(R) 1 -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. [0069] Any amine, hydroxy, or carboxyl side chain on the compounds disclosed herein can be esterified or amidified. The procedures and specific groups to be used to achieve this end is known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated by reference herein in its entirety. [0070] A "prodrug" refers to an agent that is converted into the parent drug 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. An example, without limitation, of a prodrug would be 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. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. [0071] The term "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). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups. The term "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 - 30 - WO 2005/047899 PCT/US2004/036952 contains at least one atom which is different from carbon. The term "heteroaromatic" or "heteroaryl" refers to an aromatic group which contains at least one heterocyclic ring. [00721 Examples of 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. [0073] Examples of heteroaryl ring 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, N N N Li N 1N pyrimidine, pyrazine, piperazine, triazine,
R
2 ,R ,and , where R is as defined herein. [00741 As used herein, the term "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. An "alkene" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and 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. [0075] 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 "CI-C 4 alkyl" or similar designations. By way of example only, "C 1
-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. -31- WO 2005/047899 PCT/US2004/036952 [00761 The alkyl group may be substituted or unsubstituted. When substituted, 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, 0-carbamyl, N-carbamyl, 0-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, 0-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. Typical 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. Wherever a substituent is described as being "optionally substituted" that substituent may be substituted with one of the above substituents. [00771 The tenn "alkylene" refers to an alkyl group, as defined here, which is a biradical and is connected to two other moieties. Thus, methylene (-CH 2 -), ethylene
(-CH
2
CH
2 -), proylene (-CH 2
CH
2
CH
2 -), isopropylene (-CH 2
-CH(CH
3 )-), and isobutylene
(-CH
2
-CH(CH
3
)-CH
2 -) are examples, without limitation, of an alkylene group. [0078] 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). [0079] An "O-carboxy" group refers to a RC(=O)O- group, where R is as defined herein. [0080] A "C-carboxy" group refers to a -C(=O)OR groups where R is as defined herein. [0081] An "acetyl" group refers to a -C(=O)CH 3 , group. [0082] A "trihalomethanesulfonyl" group refers to a X 3 CS(=0) 2 - group where X is a halogen. [0083] A "cyano" group refers to a -CN group. [0084] An "isocyanato" group refers to a -NCO group. [0085] A "thiocyanato" group refers to a -CNS group. [0086] An "isothiocyanato" group refers to a -NCS group. [0087] A "sulfinyl" group refers to a -S(=O)-R group, with R as defined herein. -32- WO 2005/047899 PCT/US2004/036952 [0088] A "S-sulfonamido" group refers to a -S(=O) 2 NR, group, with R as defined herein. [00891 A "N-sulfonamido" group refers to a RS(=0) 2 NH- group with R as defined herein. [00901 A "trihalomethanesulfonamido" group refers to a X 3 CS(=0) 2 NR- group with X and R as defined herein. [0091] An "O-carbamyl" group refers to a -OC(=O)-NR, group-with R as defined herein. [00921 An "N-carbamyl" group refers to a ROC(=0)NH- group, with R as defined herein. [0093] An "O-thiocarbamyl" group refers to a -OC(=S)-NR, group with R as defined herein. [00941 An "N-thiocarbamyl" group refers to an ROC(=S)NH- group, with R as defined herein. [0095] A "C-amido" group refers to a -C(=O)-NR 2 group with R as defined herein. [0096] An "N-ainido" group refers to a RC(=O)NH- group, with R as defined herein. [0097] The term "perhaloalkyl" refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms. [00981 When two substituents and the carbons to which they are attached form a ring, it is meant that the following structure:
R
2 R, is representative of the following structure: - 33 - WO 2005/047899 PCT/US2004/036952 [0099] In the above example, R 1 and R 2 and the carbons to which they are attached form a six-membered aromatic ring. [0100] When two substituents and the nitrogen to which they are attached form a fused heteroaryl, or heterocyclic ring; it is meant that the following structure: R1 R2 is representative of, for example, the following structures: -- N -N [01011 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, 0-carbamyl, N-carbamyl, 0-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, 0-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references such as Greene and Wuts, above. [01021 Certain of the compounds disclosed herein may exist as stereolsomers including optical isomers. The scope of the present disclosure includes all stereoisomers and both the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are well known to those of ordinary skill in the art. [01031 In yet another aspect, disclosed herein is a compound selected from the group consisting of H N-N H NN ' H N-N H 0 0 N N N HO O 0 -34- WO 2005/047899 PCTIUS2004/036952 Br NH C NH N 0 N N N o N>~ 0 N'~ o o 0 0 r Ni Ni N H N HN 0 HN 0 0 N N 'KJ J N N H 'iH H and N 0 Br N N H H [01041 The schemes, set forth below, provide the general scheme for the synthesis of the compounds disclosed herein. Scheme 1 depicts the synthesis of the compounds of Formula I. - 35 - WO 2005/047899 PCTIUS2004/036952 Scheme 1 0 H 0 N-NH N 'NH 2 solvent H H + O=C=N-R 5 N Rd rt, overnight Re R5 solvent
R
4
R
3 base Cl X'N,R2 rt, 3h N-N R 4 R3 NN S X .R2 R6
R
5 [01051 Scheme 2 depicts the synthesis of the compounds of Formula I. Scheme 2 PG N' R 3 PG'N'R3 X1 O
NO
2 + O? 1 solvent LGO N OH LGO 0 + N N OH X2 H rt, overnight N
R
1 LG = Leaving group/protecting group coupling rt, overnight PG = Protecting group reagent o PG, -R 3 solvent N
F
3 R base HN O heat X0 O N overnight PGO N N,R2 N X2
X
2 N X 1 Deprotect R2
R
1 -36- WO 2005/047899 PCT/US2004/036952 [0106] Scheme 3 depicts the synthesis of the compounds of Formula II. Scheme 3 1) amine 6o 'eR HO 0 coupling solvent 6 reagent RN O base N O H O=C=N-R 3 R
R
1
NR
2 PG rt, 5h R 1 N rt, overnight R1 N N'R 3 2) deprotect H I alkylation
R
6 R5"N 0 O
R
1 N N'R3 I I
R
2
R
4 [01071 In another aspect, disclosed herein is the use of the FPRL1 receptor as a screening tool to identify compounds effective in treating inflammation. In some embodiments, such use may be affected through a method of screening for a compound able to affect one or more activities of a FPRL1 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 FPRL1 receptor, provided that the cell does not have functional FPRL1 receptor expression from endogenous nucleic acid, and b) determining the ability of the test compound to affect one or more activities of the FPRL1 receptor, and comparing that ability with the ability of the test compound to affect the one or more FPRL1 receptor activities in a cell not comprising the recombinant nucleic acid; where the recombinant nucleic acid comprises a FPRL1 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) a derivative of either nucleic acid molecule in i) or ii), where the derivative encodes a receptor having one or more activities of the FPRL1 receptor and comprises at least 20 contiguous nucleotides which can hybridize under stringent hybridization conditions to the compliment of the nucleic acid of SEQ ID NO:1. [0108] In certain embodiments, the FPRL1 receptor nucleic acid encodes the amino acid sequence of a SEQ ID NO:2 derivative comprising at least 20 contiguous -37- WO 2005/047899 PCT/US2004/036952 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. [0109] In some embodiments, 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. [0110] In another aspect, 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, II, or II, wherein the compound activates a FPRL1 receptor subtype. [0111] In yet another aspect, 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, II, or III, whereby one or more symptoms of the inflammation is reduced. [0112] In certain embodiments, the above method further comprises the step of identifying an individual in need of inflammatory treatment prior to the contacting step. [0113] In other embodiments, the compound of Formula I, II, or III selectively activates the FPRL1 receptor subtype. [0114] In another aspect, 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, II, or M. In certain embodiments, 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. In other embodiments, the inflammatory response is associated with rheumatoid arthritis, Azheimer's disease or asthma. In yet other embodiments, the inflammatory response results from physical injury, including physical trauma and radiation exposure. [0115] In another aspect, the present disclosure relates to a method of inducing vasodilation to treat or prevent a vasocontractive response or condition, comprising: -38 - WO 2005/047899 PCT/US2004/036952 administering to a subject an ettective vasodilatory amount of a compound of Formula I, II, or III. In certain embodiments, 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. [01161 In a further aspect, 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, II, or III. In some embodiments, 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 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. In other embodiments, 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. [01171 In yet another aspect, 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, I, or III. 101181 In certain embodiments, 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. H N-N H | N -I\ N N N H N-N H 0a0 ~N N'SA- N ~ 0 O O HO N Compound I Compound 2 -39- WO 2005/047899 PCTIUS2004/036952 Br aNH O Cl aNH00 N N 0 N 0 N N N 0 0 N1~ Compound 3 Compound 4 NN HN HN 0 HN"" HN 0~ 0 . N flN~ N N H H H H Compound 5 Compound 6 Br N 0 Compound 7 [0119] In another aspect, disclosed herein is 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 II, or Formiula III as defined herein, whereby one or more symptoms of the pain are reduced. - 40 - WO 2005/047899 PCT/US2004/036952 [0120] Another aspect disclosed herein is the discovery that the disclosed FPRL1 compounds are specific agonists of the FPRL1 receptor. Therefore, these agonists are expected to bind to the FPRL1 receptor and induce anti-inflammatory responses. The agonists of FPRL1 receptor described herein can be used to treat acute or chronic inflammation. [0121] Thus, in some embodiments, the compound of Formula I, Formula II, or Formula III activates the FPRL1 receptor. In certain embodiments, the compound may selectively activate the FPRL1 receptor subtype, but not the FPR or FPRL2 receptor. [0122] The term "activate" refers to increasing the cellular function of the FPRL1 receptor. The receptor function is preferably the interaction with a natural binding partner. The term "natural binding partner" refers to a molecule that binds to a FPRL1 receptor in a cell. [0123] In certain embodiments, 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, Crolm'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. [0124] In another aspect, disclosed herein is 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 II, or Formula III, as defined herein; and determining if said at least one compound reduces inflammation in the subject. [01251 In yet another aspect, disclosed herein is a method of identifying a compound of Formula I, Formula II, or Formula III which is an agonist of the FPRLl receptor, the method comprising contacting a FPRL1 receptor with at least one compound of Formula I, Formula II, or Formula III, as defined herein; and determining any increase in activity level of the FPRL1 receptor so as to identify a compound of Formula I, Formula II, or Formula III , which is an agonist of the FPRL1 receptor. -41- WO 2005/047899 PCT/US2004/036952 [0126] In the context of present disclosure, 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. [01271 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. [0128] The term "therapeutically 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. [0129] In a further aspect, disclosed herein is a method of identifying a compound which is an agonist of a FPRL1 receptor, the method comprising culturing cells that express the FPRL1 receptor; incubating the cells with at least one compound of Formula I, Formula II, or Formula III as defined herein; and determining any increase in activity of the FPRL1 receptor so as to identify a compound of Formula I, Formula II, or Formula III which is an agonist of a FPRL1 receptor. [01301 In certain embodiments, the cultured cells overexpress said FPRL1 receptor. In other embodiments, the identified agonist is selective for the FPRL1 receptor. [01311 In another aspect, disclosed herein is a pharmaceutical composition comprising a compound of Formula I, Formula II, or Formula Ill as described above, and a physiologically acceptable carrier, diluent, or excipient, or a combination thereof. [0132] The term "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. Pharmaceutical 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, -42 - WO 2005/047899 PCT/US2004/036952 methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. [0133] The term "carrier" defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example dimethyl sulfoxide (DMSO) is a commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or tissues of an organism. [01341 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. [01351 The term "physiologically acceptable" defines a carrier or diluent that does not abrogate the biological activity and properties of the compound. [01361 The pharmaceutical 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). Techniques for formulation and administration of the compounds of the instant application may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990. [01371 Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections. [0138] Alternately, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into the are of pain, often in a depot or sustained release formulation. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. [0139] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, - 43 - WO 2005/047899 PCT/US2004/036952 granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes. [0140] Pharmaceutical 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. [01411 For injection, 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. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. [0142] For oral administration, 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. Pharmaceutical preparations 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, hydroxypropylnethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. [01431 Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, tale, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be - 44 - WO 2005/047899 PCT/US2004/036952 added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. [0144 Pharmaceutical preparations, 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. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All fonnulations for oral administration should be in dosages suitable for such administration. [0145] For buccal administration, the compositions may take the fonn of tablets or lozenges formulated in conventional manner. [0146] For administration by inhalation, 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. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., 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. [0147] 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. [0148] Pharmaceutical formulations 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 - 45 - WO 2005/047899 PCT/US2004/036952 suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly, concentrated solutions. [01491 Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. [0150] 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. [01511 In addition to the formulations described previously, 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. Thus, for example, 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. [0152] 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. A common cosolvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 8 0 TM , and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the 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. [01531 Alternatively, 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. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those -46- WO 2005/047899 PCT/US2004/036952 skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed. [0154] Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions. Phannaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acids or base forms. [0155] Pharmaceutical 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. [0156] 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. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1). Typically, 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. Thus, in most instances, 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. Where no human dosage is established, as will be the case for newly-discovered pharmaceutical compounds, a suitable human dosage can be inferred from ED 50 or ID 50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals. -47 - WO 2005/047899 PCT/US2004/036952 [01571 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 ing, 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. Alternatively the compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day. Thus, 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. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years. [0158] 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). The MEC will vaty 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. [0159] Dosage intervals can also be determined using MEC value. 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%. [01601 In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration. [01611 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. [0162] 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 -48- WO 2005/047899 PCT/US2004/036952 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 fonn 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. [0163] It will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure. Example 1: Receptor Selection and Amplification Technology Assay [0164] The functional receptor assay, Receptor Selection and Amplification Technology (R-SAT), was used to investigate the pharmacological properties of known and novel FPRL1 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. [01651 Briefly, 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 p-galactosidase plasmid DNA. All receptor and G protein constructs used were in the pSI-derived mammalian expression vector (Promega Inc) as described previously. The FPRL1 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. With both methods, cells were then grown in a humidified atmosphere with 5% ambient CO 2 for five days. Media was then removed from the plates and marker gene activity was measured by the addition of the p-galactosidase substrate o-nitrophenyl p-D-galactopyranoside (ONPG, in PBS with 0.5% NP-40). The resulting colorimetric reaction was measured in a -49- WO 2005/047899 PCT/US2004/036952 spectrophotometric plate reader (Titertek Inc.) at 420 nm. All data were analyzed using the computer program XLFit (IDBSm). Efficacy is the percent maximal activation compared to activation by a control compound (WKYMVm in the case of FPRL1). pECso is the negative of the log(ECsa), where EC 50 is the calculated concentration in Molar that produces 50% maximal activation. [01661 These experiments have provided a molecular profile, or fingerprint, for each of these agents at the human FPLR1 receptor. As can be seen in Table 1, these compounds selectively activate FPRL1 receptors relative to mock transfected cells. TABLE 1 Compound Generic pECso %Efficacy Structure 1 Formula I 5.9 90 2 Formula I 5.6 72 3 Formula II 5.8 112 4 Formula II 5.7 75 5 Formula II 5.6 98 6 Formula III 5.6 102 7 Formula III 7.3 67 Efficacy is relative to the ligand WKYMVm. Example 2: FPRL1 Receptor Binding Assay [0167] Using the following reagents, supplies, and methods, the ability of the compounds disclosed herein to bind to the FPRL1 receptors can be readily determined in a receptor binding assay. [01681 1. Grow FPRL1 receptor-transfected COS cells (or another transfected cell line that does not endogenously express the FPRL1 receptors may be substituted) in a suitable growth medium in 24-well culture plates. [0169] 2. Prepare radiolabeled assay solutions by mixing 245 pl of 0.25 nM [1 25 1]WKYMVm working solution with 5 p1 of the following (one per solution): 50 mM unlabeled WKYMVm working solution, 0.25 nM [1251] WKYMVm working solution, HEPES buffer only, or 50x test compound. [01701 3. Aspirate medium from 24-well plates using a Pasteur pipet attached to a vacuum source. Do not wash cells. -50- WO 2005/047899 PCT/US2004/036952 [01711 4. Add 250 pl 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. Terminate the incubation by aspirating the radioactive solution with a 24-well Brandel cell harvester. Wash the wells three times with 0.5 ml ice-cold HEPES buffer using the cell harvester. [0173] 6. Aspirate the solution from the wells with a micropipettor and transfer to 12 x 75-rum polystyrene test tubes. Analyze with a gamma counter (Packard, Cobra 11). [0174] 7. Determine specific binding and calculate the IC,, values. Example 3: Determination of Changes in Cytosolic Calcium in Transfected HL-60 Cells [0175] 1. HL-60 cells transfected with FPRL1 or a control receptor at a density 1-3 x 106 cells/ml are washed with phosphate-buffered saline. [01761 2. Cells are loaded with 2 pAM Fura-2 and analyzed with respect to the rise in intracellular calcium in the presence or absence of varying concentration of compound. [0177] 3. The response is compared to that elicited by the application of the standard reference ligand WKYMVm when tested at 1 00nM. [0178] Intracellular free calcium concentrations are calculated using the formula: [Ca 2 +]= KA(F - Fmin) Fmax - F where K for Fura-2 is 224 nM, Fmax is the fluorescence in the presence of 0.04% Triton-X100 and Fmsi 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 FPRL1 specific compounds. [0179] 1. 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. - 51 - WO 2005/047899 PCT/US2004/036952 [01801 2. Animals were injected intraperitoneally with vehicle, ibuprofen (100 mg/kg) or various doses of FPRL1 specific compounds of Fomula I, II or II. [0181] 3. Acute inflammatory pain was created by injecting 0.10 ml of 2% k carrageenan (type IV; isolated from two species of seaweed Gigartina aciculaire and G. pistillata) into the dorsal surface of the left hind paw 15 min after compound administration. [0182] 4. Response latencies were then measured at 60, 90, 120 and 180 min following compound administration in order to detect possible changes in thermal sensitivity. A significant decrease in the hot plate latency was interpreted as the presence of thermal hyperalgesia. [0183] 5. Additionally, paw thickness was determined, in order to quantify local edema, immediately following testing at the 180 min time-point. [0184] The results are indicated in Figures 1-4. As shown in Figures 1-3, administration of Compound 7 reduced thermal hyperalgesia. As shown in Figure 4, administration of Compound 7 also prevents edema formation. Example 5: Sequences for FPRL1 [01851 SEQ ID NO:1, below, is the DNA sequence encoding the FPRL1 receptor. SEQ ID NO:2, below, is the polypeptide sequence for the FPRL1 receptor. SEQ ID NO:1: 1 ggcacgagga acaacctatt tgcaaagttg gcgcaaacat tcctgcetga caggaccatg 61 gacacaggtt gtagagatag agatggctct ggctgtgcat tcagoagatt ctgtagatag 121 aattaatagg acttggatgg gattgtggtg agagaaagtg aaatgaaaga taagttctag 181 tttggaagtt ttaacaactg aatgtttaaa ctcaaataga cacaaaatat tggaagagtg 241 gcaggtttgg gaggatgaga caatcaactg ttt~gttgag ccacgttagg tttgaaatgt 301 ctacgggatc ccgtggggag aggttatatc agactggagc accagagaga ggccaaggct 361 gatagtttag atgaaaagag agcatgatat tttaagccct gagactggat aatatcacct 421 atagaaagac tatatagaga taagagaggt ggggaacaag taaaagctgc gggacactcc 481 taaatttaga gtcaaattta gagcagaaaa tactagcaaa ggggactgaa aaeggtggc 541 caattgagt tcaaatgcaa gtgaaagtgt gttgtgtgta catttatcat ctcatggcac 601 aggaaaaacg tgatttaagg agaaggaagc gatccaat9g gaagaagaga tccaatggat 661 catctatcac gaagatattg agataagaac caatatggat ttgcacccac tgcatttgca 721 gccttgaggt cataagcatc ctcaggaaaa tgcaccaggt gctgctggca agatggaaac 781 caacttctcc actcctctga atgaatatga agaagtgtcc tatgagtctg ct9gctacac 841 tgttctgcgg atcctcccat tggtggtgct tggggtcac tttgtcctcg gggtcctggg 901 caatgggctt gtgatctggg tggctggatt ccggatgaca cgcacagtca ccaccatctg 961 ttacctgaac ctggccctgg ctgacttttc tttcacggcc acattaccat tcetcattgt 1021 ctccatggcc atgggagaaa aatggccttt tggctggttc ctgtgtaagt taatcacat 1081 cgtggtggac atcaacatct ttggaagtgt cttcttgatt ggtttcattg cactggaccg 1141 ctgcatttgt gtcctgcatc cagtctgggc ccagaaccac cgcactgtga gtctggacat 1201 gaaggtgatc gtcggacctt ggattcttgo tetagtcctt accttgccag ttttcctctt 1261 tttgactaca gtaactattc caaatgggga cacatactgt actttcaact ttgcatactg 1321 gggtggcacc cctgaggaga ggctgaaggt ggccattacc atgctgacag coagagggat 1381 tatccggttt gtcattggct ttagcttgcc gatgtccatt gttgccatct gctatgggct 1441 cattgcagcc aagatccaca aaaagggcat gattaaatcc agccgtccct tacgggtcct 1501 cactgctgtg gtggcttctt tcttcatctg ttggtttccc tttcaactgg ttgcccttct 1561 gggcaccgtc tggctcaaag agatgttgtt ctatggcaag tacaaaatca ttgacatcct 1G21 ggttaaccca acgagctccc tggccttctt caacagctgc ctcaacccca tgetttacgt 1681 ctttgtgggc caagacttcc gagagagact gatccactec ctgcccacca gtctggagag 1741 ggccctgtct gaggactcag ccccaactaa tgacacggct gccaattctg cttcacctcc 1801 tgcagagact gagttacagg caatgtgagg atggggtcag ggatattttg agttctgttc _ 52 - WO 2005/047899 PCT/US2004/036952 1861 atcctaccct aatgccagtt ccagcttcat ctaccttga gtcatattga ggcattcaag 1921 gatgcacagc tcaagtattt attcaggaaa aatgattttg tgtccctgat ttggggctaa 1981 gaaatagaca gtcaggctac taaaatatta gtgttatttt ttgttttttg acttctgcct 2041 ataccctggg gtaagtggag ttgggaaata caagaagaga aagaccagtg gggatttgta 2101 agacttagat gagatagcgc ataataaggg gaagacttta aagtataaag taaaatgttt 2161 gctgtaggtt Ltttatagct attaaaaaaa atoagattat ggaagttttc ttctattttt 2221 agtttgctaa gagttttctg tttctttttc ttacatcatg agtggacttt gcattttatc 2281 aaatgcattt tctacatgta ttaagatggt catattatto ttcttctttt atgtaaatca 2341 ttataaataa tgttcattaa gttctgaatg ttaaactact cttgaattcc tggaataaac 2401 cacacttagt cctgatgtac tttaaatatt tatatotcac aggagttggt tagaatttct 2461 gtgtttatgt ttatatactg ttatttcact ttttctacta tccttgctaa gttttcatag 2521 aaaataagga acaaagagaa acttgtaatg gtctctgaaa aggaattgag aagtaattcc 2581 tctgartctg ttttctggtg ttatatcttt attaatatt cagaaaaatt c SEQ ID NO:2:, METNFSTPLNEYEEVSYESAGYTVLRILPLVVLGVTFVLGVLCN GLVI WVACFRMTRTVTTI CYLNIIALADFSFTATLPFLIVSMAMGEKWPFGWFLCI(LIE IVVDI4LECSVFLIGIALDRCICVLHPVWAQNHRTVSLAMK-VIVGPWILALVLTLPV FLFLTTVTI PNCDTYCTFNFASWGGTPEERLKVAITMLTARGI IRFVIGFSLPMS IVA ICYGLIAACIHKKGMIKSSRFLRVLTAVVASFFICWFPFQLVALLGTVWLKEMLFYGK flU IDILVNPTSSLAFFNSCLNPMLYVFVGQDFRERLIHSLPTSLERALSEDSAPTND TAANSASPPAETELQAM - 53 -

Claims (87)

1. The use of the FPRL1 receptor as a tool to identify compounds effective in treating inflammation and associated pain.
2. The use of the FPRL1 resceptor as a screening tool to identify compounds effective in treating inflammation and associated pain.
3. The use of compounds specifically active at the FPRL1 receptor as therapeutics for treating inflammation and associated pain.
4. The prophylactic use of compounds specifically active at the FPRL1 receptor as therapeutics for blocking inflammation and associated pain.
5. A method of screening for a compound able to affect one or more activities of a FPRL1 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 FPRL1 receptor, provided that said cell does not have functional FPRL1 receptor expression from endogenous nucleic acid, and b) determining the ability of said test compound to affect one or more activities of said FPRL1 receptor, and comparing said ability with the ability of said test compound to affect said one or more FPRL1 receptor activities in a cell not comprising said recombinant nucleic acid; wherein said recombinant nucleic acid comprises a FPRL1 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) a derivative of either nucleic acid molecule in i) or ii), wherein said derivative encodes a receptor having one or more activities of said FPRLl receptor and comprises at least 20 contiguous nucleotides which can hybridize under stringent hybridization conditions to the compliment of the nucleic acid of SEQ ID NO:1.
6. The method of Claim 5, wherein said FPRL1 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. - 54- WO 2005/047899 PCT/US2004/036952
7. 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, II, or Ii, wherein the compound activates a FPRL1 receptor subtype.
8. The method of Claim 7 wherein 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, Croln'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, systemic lupus erythematosus, chronic renal disease, cardiovascular disease, and hypertension or chemical injury.
9. A method of identifying a compound which is an agonist of the FPRL1 receptor, the method comprising: contacting a FPRL1 receptor with at least one test compound of Formula I, II, or III; and determining any increase in activity level of said FPRL1 receptor so as to identify a test compound which is an agonist of the FPRL1 receptor.
10. A method of identifying a compound which is an agonist of a FPRL1 receptor, the method comprising: culturing cells that express said FPRL1 receptor; incubating the cells or a component extracted from the cells with at least one test compound of Formula I, II, or ff1; and determining any increase in activity of said FPRL1 receptor so as to identify a test compound which is an agonist of a FPRL1 receptor.
11. The method of Claim 10, wherein the cultured cells overexpress said FPRL1 receptor.
12. The method of Claim 9 or 10, wherein the identified agonist is selective for the FPRLl receptor.
13. A method for treating inflammation comprising contacting an individual suffering from inflammation with an effective amount of at least one compound of Formula I, I, or II, - 55 - WO 2005/047899 PCT/US2004/036952 whereby one or more symptoms of the inflammation is reduced.
14. The method of Claim 13 further comprising the step of identifying an individual in need of inflammatory treatment prior to the contacting step.
15. The method of Claim 13, wherein said compound of Formula I, II, or III selectively activates the FPRL1 receptor subtype.
16. The method of Claim 13, wherein 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.
17. The method of Claim 13, wherein the inflammatory response is associated with rheumatoid arthritis, Azheimer's disease or asthma.
18. The method of Claim 13, wherein the inflammatory response results from physical injury, including physical trauma and radiation exposure.
19. 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, II, or III.
20. 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, II, or III.
21. A method of Claim 20, wherein 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.
22. A method for antagonizing a vasoconstrictive response to a sulfidopeptide leukotriene in a subject, comprising: administering to the subject a composition of Formula I, II, or III.
23. The method of Claim 22, wherein 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 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. - 56 - WO 2005/047899 PCT/US2004/036952
24. The method of Claim 22, wherein 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.
25. 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, II, or Ill.
26. A compound of Formula I H N-N R 4 R 3 N S RI R 2 C R5 or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein Ri is selected from the group consisting of C 1 -C 10 straight chained or branched alkylene, oxygen, sulfur, NQ, CHCN, C=O, C=S, C=NQ, S=O, S(=0) 2 , C=NOQ, wherein Q is independently selected from the group consisting of hydrogen, CI-C10 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C 2 -Cio straight chained or branched alkenyl optionally substituted with an aryl or heteroaryl, C 2 -C 10 straight chained or branched alkynyl optionally substituted with an aryl or heteroaryl, C 3 -Cio cycloalkyl, and C 5 -Cio cycloalkenyl; each of R 2 , R 3 , R 4 , and R 5 is independently selected from the group consisting of hydrogen, C 1 -C 10 straight chained or branched alkyl, C 2 -C 1 0 straight chained or branched alkenyl, C 2 -C 1 0 straight chained or branched alkynyl, C 3 -C 10 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, -OR 7 , -N(R 7 ) 2 , -CN, -C(=Z)R7, -C(=Z)OR7, -C(=Z)N(R7)2, -N(Ry)-C(=Z)R7, -N(R 7 )-C(=Z)N(R 7 ) 2 , -OC(=Z)R 7 , and -SR 7 , wherein Z is oxygen or sulfur; and wherein each R 7 is independently selected from the group consisting of hydrogen, C 1 -C1 0 straight chained or branched alkyl -57- WO 2005/047899 PCT/US2004/036952 optionally substituted with an aryl or heteroaryl, C 2 -Cio 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 -C1O cycloalkyl, and C 5 -C 10 cycloalkenyl; or R 3 and R 4 and the nitrogen to which they are attached form a fused heteroaryl, or heterocyclic ring. R 6 may be present 0-5 times and is independently selected from the group consisting of hydrogen, C 1 -C 4 straight chained or branched alkyl, cycloalkyl, aryl or heteroaryl optionally substituted, hydroxy, nitro, amino, halogen, sulphonate, perhaloalkyl, -OR 7 , -N(R 8 ) 2 , -CN, -C(=Z)Rs, -C(=Z)ORs, -C(=Z)N(R 8 ) 2 , -N(Rs)-C(=Z)Rs, -N(R 8 )-C(=Z)N(Rs) 2 , -OC(=Z)Rs, and SR 8 , wherein Z is oxygen or sulfur; and wherein each R 8 is independently selected from the group consisting of hydrogen, C 1 -C 10 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C 2 -C 10 straight chained or branched alkenyl optionally substituted with an aryl or heteroaryl, C 2 -C 1 0 straight chained or branched alkynyl optionally substituted with an aryl or heteroaryl, C 3 -C 1 o cycloalkyl, and C 5 -C 10 cycloalkenyl; or "R 6 " form a fused aryl or heteroaryl ring
27. The compound of Claim 26, wherein R 1 is hydrogen or C 1 -C 10 straight chained alkyl.
28. The compound of Claim 26, wherein R 1 is CI-C 5 straight chained alkylene.
29. The compound of Claim 28, wherein R 1 is selected from the group consisting of methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, tert-butylene, n-pentylene, and isopentylene.
30. The compound of Claim 26, wherein R 2 is selected from the group consisting of hydrogen, hydroxy, nitro, amino, aryl, heteroaryl, -OR 7 , and -N(R 7 ) 2 , and wherein R 7 is hydrogen or C 1 -C 10 straight chained alkyl.
31. The compound of Claim 30, wherein R 7 is hydrogen or C 1 -C 3 straight chained alkyl. - 58 - WO 2005/047899 PCT/US2004/036952
32. The compound of Claim 26, wherein R 2 is selected from the group consisting of hydrogen, hydroxy, nitro, aryl, heteroaryl, methoxy, and ethoxy.
33. The compound of Claim 26, wherein 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-Cio straight chained alkyl.
34. The compound of Claim 33, wherein R 7 is hydrogen or C-C 3 straight chained alkyl.
35. The compound of Claim 26, wherein R3 is selected from the group consisting of hydrogen, nitro, aryl, heteroaryl.
36. The compound of Claim 26, wherein R 4 is selected from the group consisting of hydrogen, Cr-C 10 straight chained alkyl, hydroxy, nitro, amino, halogen, OR 7 , and -N(R 7 ) 2 , and wherein R7 is C-Cia straight chained or branched alkyl optionally substituted with an aryl or heteroaryl.
37. The compound of Claim 26, wherein R 4 is selected from the group consisting of hydrogen, C-C 3 straight chained alkyl, hydroxy, nitro, amino, halogen, -OR 7 , and -N(R 7 ) 2 , and wherein R7 is C-C 3 straight chained alkyl optionally substituted with an aryl.
38. The compound of Claim 26, wherein R 4 is selected from the group consisting of hydrogen, methyl, ethyl, hydroxy, nitro, amino, chloro, fluoro, methoxy, ethoxy, methylamino, dimethylamino, diethylamino, and benzyloxy.
39. The compound of Claim 26, wherein R 5 is selected from the group consisting of hydrogen, CI-C 10 straight chained alkyl, hydroxy, nitro, amino, halogen, perhaloalkyl, -OR 7 , and -N(R 7 ) 2 , and wherein R 7 is C-Cio straight chained or branched alkyl optionally substituted with an aryl or heteroaryl.
40. The compound of Claim 26, wherein Rs is selected from the group consisting of hydrogen, CI-C 3 straight chained alkyl, hydroxy, nitro, amino, halogen, perhaloalkyl, -OR 7 , and -N(R 7 ) 2 , and wherein R 7 is CI -C 3 straight chained alkyl.
41. The compound of Claim 26, wherein R 5 is selected from the group consisting of hydrogen, hydroxy, chloro, bromo, trifluoromethyl, and methoxy.
42. The compound of Claim 26, wherein R 6 is hydrogen.
43. The compound of Claim 26, wherein R 2 and R 3 and the nitrogen to which they are attached fonn a fused heteroaryl or heterocyclic alkyl ring.
44. The compound of Claim 43, wherein the ring is a heterocyclic alkyl ring. - 59 - WO 2005/047899 PCT/US2004/036952
45. The compound of Claim 44, wherein the heterocyclic alkyl ring is selected from the group consisting of N-morpholine and pyrrole.
46. A compound selected from the group consisting of H N-N H H N-N H NCOO N N N N N N N N S 0 0 CI H N-N H COOH H N-N 0 N N N \N N N o'C 0-6 CI J) 'N. H N-N H N-N H N N N S N H NN O 0 O~a 0 H N-N H H N-N H N N N N 0 0 0 0 NN H NN H - j N N\ N 'N - NHH N-N H N N. N 1\ 'N N) N 00 HO60N WO 2005/047899 PCT/US2004/036952 H N-N H N /\ N H N-N j H N NN N 00 ,and
47. A compound of Formula II R 3 R 1 0 N (II) N X, N>X R2 or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein each of X 1 and X 2 is independently oxygen or sulfur; R 1 is selected from the group consisting of C 1 -C 10 straight chained or branched alkylene, oxygen, sulfur, NQ, CHCN, C=O, C=S, C=NQ, S=O, S(=0) 2 , C=NOQ wherein Q is selected from the group consisting of hydrogen, C 1 -C 10 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C 2 -C 1 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 10 cycloalkyl, and C 5 -C 10 cycloalkenyl; each of R 2 , R 3 , is independently selected from the group consisting of hydrogen, C1-Cio straight chained or branched alkyl, C 2 -Cio straight chained or branched alkenyl, C 2 -Cio straight chained or branched alkynyl, C 3 -Cio cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, -OR 7 , -N(R 7 ) 2 , -CN, -C(=Z)R 7 ,-C(=Z)OR 7 , -C(=Z)N(R 7 ) 2 , -N(R7)-C(=Z)R7, -N(R 7 )-C(=Z)N(R 7 ) 2 , -OC(=Z)R 7 , , and -SR 7 , - 61 - WO 2005/047899 PCT/US2004/036952 wherein Z is oxygen or sulfur; and wherein each R 7 is independently selected from the group consisting of hydrogen, C1-C 10 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C 2 -C 10 straight chained or branched alkenyl optionally substituted with an aryl or heteroaryl, C 2 -C 10 straight chained or branched alkynyl optionally substituted with an aryl or heteroaryl, C 3 -C 10 cycloalkyl, and C 5 -Cio cycloalkenyl.
48. The compound of Claim 47, wherein R 1 is selected from the group consisting of oxygen and NQ, wherein Q is selected from the group consisting of hydrogen, C-C 5 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl.
49. The compound of Claim 48, wherein Q is C 1 -C 3 straight chained or branched alkyl.
50. The compound of Claim 48, wherein Q is selected from the group consisting of methyl, ethyl, and propyl.
51. The compound of Claim 48, wherein Q is methyl.
52. The compound of Claim 47, wherein R 2 is selected from the group consisting of hydrogen, C 1 -C 10 straight chained or branched alkyl, C 3 -C 1 0 cycloalkyl, and optionally substituted aryl.
53. The compound of Claim 52, wherein R 2 is substituted aryl.
54. The compound of Claim 53, wherein R 2 is selected from the group consisting of 4-alkylphenyl, 4-alkoxyphenyl, 4-alkoxycarbonylphenyl.
55. The compound of Claim 53, wherein R 2 is selected from the group consisting of 4-methylpheynl, 4-ethoxyphenyl, and 4-ethoxycarbonylphenyl.
56. The compound of Claim 47, wherein R 3 is selected from the group consisting of hydrogen, C 1 -C 10 straight chained or branched alkyl, C 3 -Cia cycloalkyl, and optionally substituted aryl.
57. The compound of Claim 56, wherein R 3 is substituted aryl.
58. The compound of Claim 57, wherein R 3 is selected from the group consisting of 4-alkyIphenyl, 4-alkoxyphenyl, and 4-halophenyl.
59. The compound of Claim 58, wherein R 3 is selected from the group consisting of 4-chlorophenyl, 4-bromophenyl, and 4-methoxyphenyl.
60. A compound of Formula III - 62 - WO 2005/047899 PCT/US2004/036952 R 6 R'N 00 (III) 0R R, CN N'R4 R 2 R 3 or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein each of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from the group consisting of hydrogen, C 1 -C 10 straight chained or branched alkyl, C 2 -Cio straight chained or branched alkenyl, C 2 -Cio straight chained or branched alkynyl, C 3 -Cio cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaiyl, substituted or unsubstituted heterocyclic ring, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, -OR 7 , -N(R 7 ) 2 , -CN, -C(=Z)R 7 ,-C(=Z)OR 7 , -C(=Z)N(R 7 ) 2 , -N(R7)-C(=Z)R7, -N(R 7 )-C(=Z)N(R 7 ) 2 , -OC(=Z)R 7 , , and -SR 7 wherein Z is oxygen or sulfur; and wherein each R 7 is independently selected from the group consisting of C 1 -C 10 straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C 2 -Cio straight chained or branched alkenyl optionally substituted with an aryl or heteroaryl, C 2 C 10 straight chained or branched alkynyl optionally substituted with an aryl or heteroaryl, C 3 -Cio cycloalkyl, and C 5 -C 10 cycloalkenyl; or R 3 and R 4 and the nitrogen to which they are attached form a fused heteroaryl, or heterocyclic ring; R 5 and R 6 and the nitrogen to which they are attached form a fused heteroaryl, or heterocyclic ring; or R 1 , R 2 , the carbon to which R 1 is attached, and the nitrogen to which R 2 is attached form a fused heteroaryl, or heterocyclic ring.
61. The compound of Claim 60, wherein R 1 is selected from the group consisting of hydrogen and optionally substituted C 1 -C 10 straight chained or branched alkyl.
62. The compound of Claim 61, wherein R 1 is Ci-C 5 straight chained alkyl optionally substituted with an aryl or heteroaryl ring. - 63 - WO 2005/047899 PCT/US2004/036952
63. The compound of Claim 62, wherein said aryl ring is phenyl.
64. The compound of Claim 62, wherein said heteroaryl ring comprises nitrogen.
65. The compound of Claim 64, wherein said heteroaryl ring is indole.
66. The compound of Claim 61, wherein said R 1 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.
67. The compound of Claim 60, wherein said R, is selected from the group consisting of methyl, indolylmethyl, benzyl, and sec-butyl.
68. The compound of Claim 60, wherein R 1 , R 2 , the carbon to which R 1 is attached, and the nitrogen to which R 2 is attached form a fused heteroaryl, or heterocyclic ring.
69. The compound of Claim 68, wherein said heterocyclic ring is pyrolidine.
70. The compound of Claim 60, wherein R 2 , R 3 , and R 5 are each independently selected from the group consisting of hydrogen, C 1 -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.
71. The compound of Claim 70, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.
72. The compound of Claim 60, wherein R 2 , R 3 , and R 5 are hydrogen.
73. The compound of Claim 60, wherein R 4 is optionally substituted aryl.
74. The compound of Claim 73, wherein said aryl is phenyl.
75. The compound of Claim 73, wherein said aryl is optionally substituted with halo, alkoxy, alkyl, alkylthio, and perhaloalkyl.
76. The compound of Claim 73, wherein said aryl is optionally substituted with chloro, bromo, methyl, ethyl, isopropyl, methoxy, methylthio, and trifluormethyl.
77. The compound of Claim 73, wherein 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.
78. The compound of Claim 60, wherein R 6 is selected from the group consisting of optionally substituted C 1 -Cia straight chained or branched alkyl, and optionally substituted heterocyclic ring. - 64 - WO 2005/047899 PCT/US2004/036952
79. The compound of Claim 78, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, and 1-methylbutyl.
80. The compound of Claim 79, wherein said alkyl is substituted with a heterocyclic ring or a substituted amine.
81. The compound of Claim 80, wherein said heterocyclic ring is morpholine.
82. The compound of Claim 80, wherein said heterocyclic ring is piperidine or morpholine.
83. The compound of Claim 60, wherein R 6 is selected from the group consisting of 1-methyl-4-diethylaminobutyl, 2-N-morpholinoethyl, and N-benzylpiperidin 4-yl.
84. The compound of Claim 60, wherein 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.
85. The compound of Claim 84, wherein said heterocyclic ring is piperidine or benzopiperidine.
86. The compound of Claim 60, wherein R 5 and R 6 and the nitrogen to which they are attached form a substituent selected from the group consisting of 0 0 0 (-NQ -N ~-N / 0 and
87. A compound selected from the group consisting of H N-N H N H N-N H 0 N N N HO O -65- WO 2005/047899 PCT/US2004/036952 Br N NH CN O 0 N O N H 0 N N N O O 0 N> 0 N 0 0 N 0 Br 0 NN H H NN H N H N 0 H N 0 0 N N H H and 6 1 H H - 66 -
AU2004290368A 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 Abandoned AU2004290368A1 (en)

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US60/592,926 2004-07-30
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