WO2014138037A1 - Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases - Google Patents
Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases Download PDFInfo
- Publication number
- WO2014138037A1 WO2014138037A1 PCT/US2014/020245 US2014020245W WO2014138037A1 WO 2014138037 A1 WO2014138037 A1 WO 2014138037A1 US 2014020245 W US2014020245 W US 2014020245W WO 2014138037 A1 WO2014138037 A1 WO 2014138037A1
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- WO
- WIPO (PCT)
- Prior art keywords
- amino
- bromophenyl
- optionally substituted
- carbamoyl
- alkyl
- Prior art date
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- 102100021126 N-formyl peptide receptor 2 Human genes 0.000 title claims abstract description 85
- 101710109169 Formyl peptide receptor 2 Proteins 0.000 title claims abstract description 76
- 239000000556 agonist Substances 0.000 title claims abstract description 25
- 208000027866 inflammatory disease Diseases 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
- 238000011282 treatment Methods 0.000 claims abstract description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 214
- 229910052739 hydrogen Inorganic materials 0.000 claims description 102
- 239000001257 hydrogen Substances 0.000 claims description 100
- 125000003118 aryl group Chemical group 0.000 claims description 87
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 62
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 57
- 125000000623 heterocyclic group Chemical group 0.000 claims description 56
- 229910052736 halogen Inorganic materials 0.000 claims description 54
- 150000002367 halogens Chemical group 0.000 claims description 54
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 47
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
- 206010046851 Uveitis Diseases 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 208000002780 macular degeneration Diseases 0.000 claims description 15
- -1 ethyl hydrogen Chemical class 0.000 claims description 14
- 229940125634 FPR2 agonist Drugs 0.000 claims description 11
- 101000818546 Homo sapiens N-formyl peptide receptor 2 Proteins 0.000 claims description 11
- 230000029663 wound healing Effects 0.000 claims description 9
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 8
- 206010023332 keratitis Diseases 0.000 claims description 8
- 125000003367 polycyclic group Chemical group 0.000 claims description 8
- 208000015181 infectious disease Diseases 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 206010038910 Retinitis Diseases 0.000 claims description 5
- 230000001154 acute effect Effects 0.000 claims description 5
- 230000000172 allergic effect Effects 0.000 claims description 5
- 208000010668 atopic eczema Diseases 0.000 claims description 5
- 230000002458 infectious effect Effects 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- ZCVLAKQKEWQJAO-AWEZNQCLSA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-3-phenylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)NC=1C=CC(Br)=CC=1)C1=CC=CC=C1 ZCVLAKQKEWQJAO-AWEZNQCLSA-N 0.000 claims description 4
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 4
- 206010013774 Dry eye Diseases 0.000 claims description 4
- 208000000208 Wet Macular Degeneration Diseases 0.000 claims description 4
- 208000011325 dry age related macular degeneration Diseases 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- ZCVLAKQKEWQJAO-CQSZACIVSA-N (2r)-2-[(4-bromophenyl)carbamoylamino]-3-phenylpropanoic acid Chemical compound C([C@H](C(=O)O)NC(=O)NC=1C=CC(Br)=CC=1)C1=CC=CC=C1 ZCVLAKQKEWQJAO-CQSZACIVSA-N 0.000 claims description 3
- WKPPVFWLQCDKQE-ZANVPECISA-N 2-[[(2s,3s)-2-[(4-bromophenyl)carbamoylamino]-3-methylpentanoyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)[C@H]([C@@H](C)CC)NC(=O)NC1=CC=C(Br)C=C1 WKPPVFWLQCDKQE-ZANVPECISA-N 0.000 claims description 3
- 208000009137 Behcet syndrome Diseases 0.000 claims description 3
- 208000002691 Choroiditis Diseases 0.000 claims description 3
- 208000005100 Herpetic Keratitis Diseases 0.000 claims description 3
- 206010073938 Ophthalmic herpes simplex Diseases 0.000 claims description 3
- 208000003971 Posterior uveitis Diseases 0.000 claims description 3
- 125000002837 carbocyclic group Chemical group 0.000 claims description 3
- 201000000159 corneal neovascularization Diseases 0.000 claims description 3
- 208000030533 eye disease Diseases 0.000 claims description 3
- 201000010884 herpes simplex virus keratitis Diseases 0.000 claims description 3
- 230000035168 lymphangiogenesis Effects 0.000 claims description 3
- 239000000049 pigment Substances 0.000 claims description 3
- ARFPPUXKLADSLY-CQSZACIVSA-N (2r)-2-[(4-iodophenyl)carbamoylamino]-3-phenylpropanoic acid Chemical compound C([C@H](C(=O)O)NC(=O)NC=1C=CC(I)=CC=1)C1=CC=CC=C1 ARFPPUXKLADSLY-CQSZACIVSA-N 0.000 claims description 2
- VMEDZAKIZFAOJL-JTQLQIEISA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-3-methylbutanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)NC1=CC=C(Br)C=C1 VMEDZAKIZFAOJL-JTQLQIEISA-N 0.000 claims description 2
- VEYCFNXDYFEYRJ-KWQFWETISA-N (2s,3s)-2-[(4-bromophenyl)carbamoylamino]-3-methylpentanoic acid Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)NC1=CC=C(Br)C=C1 VEYCFNXDYFEYRJ-KWQFWETISA-N 0.000 claims description 2
- IPOHNVXMLANJTR-UHFFFAOYSA-N 2-[(4-bromophenyl)carbamoylamino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C=1NC2=CC=CC=C2C=1CC(C(=O)O)NC(=O)NC1=CC=C(Br)C=C1 IPOHNVXMLANJTR-UHFFFAOYSA-N 0.000 claims description 2
- ZNLCEPJDHBSVKN-UHFFFAOYSA-N 2-[(4-chlorophenyl)carbamoylamino]-3-phenylpropanoic acid Chemical compound C=1C=C(Cl)C=CC=1NC(=O)NC(C(=O)O)CC1=CC=CC=C1 ZNLCEPJDHBSVKN-UHFFFAOYSA-N 0.000 claims description 2
- ROLQGUCDHGPXCI-UHFFFAOYSA-N 2-[(4-methoxyphenyl)carbamoylamino]-3-phenylpropanoic acid Chemical compound C1=CC(OC)=CC=C1NC(=O)NC(C(O)=O)CC1=CC=CC=C1 ROLQGUCDHGPXCI-UHFFFAOYSA-N 0.000 claims description 2
- SLIMOPZXCUSPOX-UHFFFAOYSA-N 3-phenyl-2-[[4-(trifluoromethyl)phenyl]carbamoylamino]propanoic acid Chemical compound C=1C=C(C(F)(F)F)C=CC=1NC(=O)NC(C(=O)O)CC1=CC=CC=C1 SLIMOPZXCUSPOX-UHFFFAOYSA-N 0.000 claims description 2
- LENLZYPMKWPZDQ-UHFFFAOYSA-O [4-[(1-carboxy-2-phenylethyl)carbamoylamino]phenyl]-oxoazanium Chemical compound C1=CC=CC(=C1)CC(C(=O)O)NC(=O)NC1=CC=C([NH+]=O)C=C1 LENLZYPMKWPZDQ-UHFFFAOYSA-O 0.000 claims description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 44
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 4
- DMYSYIXHXMXWBW-UHFFFAOYSA-N 1-(4-bromophenyl)-3-(4-ethyl-2,5-dioxo-4-propan-2-ylimidazolidin-1-yl)urea Chemical compound O=C1C(CC)(C(C)C)NC(=O)N1NC(=O)NC1=CC=C(Br)C=C1 DMYSYIXHXMXWBW-UHFFFAOYSA-N 0.000 claims 3
- WVLHIJZNLYUXDZ-CPCISQLKSA-N (2s,3s)-2-[(4-bromo-2-fluorophenyl)carbamoylamino]-3-methylpentanoic acid Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)NC1=CC=C(Br)C=C1F WVLHIJZNLYUXDZ-CPCISQLKSA-N 0.000 claims 2
- CGBOCDQDPMBHIP-UHFFFAOYSA-N 1-(4-bromophenyl)-3-[4-methyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea Chemical compound N1C(=O)N(NC(=O)NC=2C=CC(Br)=CC=2)C(=O)C1(C)CCC1=CC=CC=C1 CGBOCDQDPMBHIP-UHFFFAOYSA-N 0.000 claims 2
- KBVPGAVCBMCSJJ-UHFFFAOYSA-N 2-[(4-bromophenyl)carbamoylamino]-n-(2-oxoazepan-3-yl)-3-phenylpropanamide Chemical compound C1=CC(Br)=CC=C1NC(=O)NC(C(=O)NC1C(NCCCC1)=O)CC1=CC=CC=C1 KBVPGAVCBMCSJJ-UHFFFAOYSA-N 0.000 claims 2
- ARRWDYXSLZNBRO-NSHDSACASA-N 2-[[(2s)-2-[(4-bromophenyl)carbamoylamino]pentanoyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)[C@H](CCC)NC(=O)NC1=CC=C(Br)C=C1 ARRWDYXSLZNBRO-NSHDSACASA-N 0.000 claims 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- DAIPOHPEAYKUFJ-JTQLQIEISA-N (2s)-2-[(4-bromo-2-fluorophenyl)carbamoylamino]-3-methylbutanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)NC1=CC=C(Br)C=C1F DAIPOHPEAYKUFJ-JTQLQIEISA-N 0.000 claims 1
- IUIJFVKTIGTRLF-AWEZNQCLSA-N (2s)-2-[(4-bromo-2-fluorophenyl)carbamoylamino]-4-methyl-n-(2-oxopropyl)pentanamide Chemical compound CC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)NC1=CC=C(Br)C=C1F IUIJFVKTIGTRLF-AWEZNQCLSA-N 0.000 claims 1
- ISXHVEOMRHCILC-INIZCTEOSA-N (2s)-2-[(4-bromo-2-fluorophenyl)carbamoylamino]-n-(2-hydroxyethyl)-3-phenylpropanamide Chemical compound C([C@@H](C(=O)NCCO)NC(=O)NC=1C(=CC(Br)=CC=1)F)C1=CC=CC=C1 ISXHVEOMRHCILC-INIZCTEOSA-N 0.000 claims 1
- BIPYNHXPZUAITO-KRWDZBQOSA-N (2s)-2-[(4-bromo-2-fluorophenyl)carbamoylamino]-n-(2-oxopropyl)-3-phenylpropanamide Chemical compound C([C@@H](C(=O)NCC(=O)C)NC(=O)NC=1C(=CC(Br)=CC=1)F)C1=CC=CC=C1 BIPYNHXPZUAITO-KRWDZBQOSA-N 0.000 claims 1
- MUTURHQUUWAQAJ-ZDUSSCGKSA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-2-phenylacetic acid Chemical compound N([C@H](C(=O)O)C=1C=CC=CC=1)C(=O)NC1=CC=C(Br)C=C1 MUTURHQUUWAQAJ-ZDUSSCGKSA-N 0.000 claims 1
- JLYOCBBJLCFPLC-AWEZNQCLSA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-4-methyl-n-(2-oxopropyl)pentanamide Chemical compound CC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)NC1=CC=C(Br)C=C1 JLYOCBBJLCFPLC-AWEZNQCLSA-N 0.000 claims 1
- WNZAMPDJJNIFRR-LBPRGKRZSA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-4-methyl-n-(2h-tetrazol-5-ylmethyl)pentanamide Chemical compound N([C@@H](CC(C)C)C(=O)NCC=1NN=NN=1)C(=O)NC1=CC=C(Br)C=C1 WNZAMPDJJNIFRR-LBPRGKRZSA-N 0.000 claims 1
- WCGZSGWHOKVWEC-AWEZNQCLSA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-4-methyl-n-[(3-oxo-1,2-oxazol-5-yl)methyl]pentanamide Chemical compound N([C@@H](CC(C)C)C(=O)NCC=1ON=C(O)C=1)C(=O)NC1=CC=C(Br)C=C1 WCGZSGWHOKVWEC-AWEZNQCLSA-N 0.000 claims 1
- MTHGEVRZTXMKTF-NSHDSACASA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-4-methylpentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)NC1=CC=C(Br)C=C1 MTHGEVRZTXMKTF-NSHDSACASA-N 0.000 claims 1
- HJRBAXCENNDVGX-AWEZNQCLSA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-n-(1,3-dihydroxypropan-2-yl)-4-methylpentanamide Chemical compound OCC(CO)NC(=O)[C@H](CC(C)C)NC(=O)NC1=CC=C(Br)C=C1 HJRBAXCENNDVGX-AWEZNQCLSA-N 0.000 claims 1
- MEHDWYDBOQKHNL-KZUDCZAMSA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-n-(2,3-dihydroxypropyl)-4-methylpentanamide Chemical compound OCC(O)CNC(=O)[C@H](CC(C)C)NC(=O)NC1=CC=C(Br)C=C1 MEHDWYDBOQKHNL-KZUDCZAMSA-N 0.000 claims 1
- UBVFESUGAURCHP-KRWDZBQOSA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-n-(2-diethoxyphosphorylethyl)-4-methylpentanamide Chemical compound CCOP(=O)(OCC)CCNC(=O)[C@H](CC(C)C)NC(=O)NC1=CC=C(Br)C=C1 UBVFESUGAURCHP-KRWDZBQOSA-N 0.000 claims 1
- PZNGVUQIYDZYCO-AWEZNQCLSA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-n-(2-hydroxy-2-methylpropyl)-4-methylpentanamide Chemical compound CC(O)(C)CNC(=O)[C@H](CC(C)C)NC(=O)NC1=CC=C(Br)C=C1 PZNGVUQIYDZYCO-AWEZNQCLSA-N 0.000 claims 1
- DMTOJWVPPCFMFC-INIZCTEOSA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-n-(2-hydroxyethyl)-3-phenylpropanamide Chemical compound C([C@@H](C(=O)NCCO)NC(=O)NC=1C=CC(Br)=CC=1)C1=CC=CC=C1 DMTOJWVPPCFMFC-INIZCTEOSA-N 0.000 claims 1
- HIASXAKDYOCRPQ-ZDUSSCGKSA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-n-(2-hydroxyethyl)-4-methylpentanamide Chemical compound OCCNC(=O)[C@H](CC(C)C)NC(=O)NC1=CC=C(Br)C=C1 HIASXAKDYOCRPQ-ZDUSSCGKSA-N 0.000 claims 1
- RQBDPOSULHFJNX-IBGZPJMESA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-n-(diethoxyphosphorylmethyl)-3-phenylpropanamide Chemical compound C([C@@H](C(=O)NCP(=O)(OCC)OCC)NC(=O)NC=1C=CC(Br)=CC=1)C1=CC=CC=C1 RQBDPOSULHFJNX-IBGZPJMESA-N 0.000 claims 1
- JSBDBKWVBGKBPM-INIZCTEOSA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-n-(diethoxyphosphorylmethyl)-4-methylpentanamide Chemical compound CCOP(=O)(OCC)CNC(=O)[C@H](CC(C)C)NC(=O)NC1=CC=C(Br)C=C1 JSBDBKWVBGKBPM-INIZCTEOSA-N 0.000 claims 1
- BKLJUMMVLHXXSH-HNNXBMFYSA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-n-(diethoxyphosphorylmethyl)pentanamide Chemical compound CCOP(=O)(OCC)CNC(=O)[C@H](CCC)NC(=O)NC1=CC=C(Br)C=C1 BKLJUMMVLHXXSH-HNNXBMFYSA-N 0.000 claims 1
- DSBITWRMTGDNTD-RISCZKNCSA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-n-[(2r)-1-hydroxypropan-2-yl]-4-methylpentanamide Chemical compound OC[C@@H](C)NC(=O)[C@H](CC(C)C)NC(=O)NC1=CC=C(Br)C=C1 DSBITWRMTGDNTD-RISCZKNCSA-N 0.000 claims 1
- SPSDTWCAZAFLNC-AWEZNQCLSA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-n-[2-(dimethylamino)-2-oxoethyl]-4-methylpentanamide Chemical compound CN(C)C(=O)CNC(=O)[C@H](CC(C)C)NC(=O)NC1=CC=C(Br)C=C1 SPSDTWCAZAFLNC-AWEZNQCLSA-N 0.000 claims 1
- SJBYUKPOGWWLGD-SFHVURJKSA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-n-[di(propan-2-yloxy)phosphorylmethyl]-4-methylpentanamide Chemical compound CC(C)OP(=O)(OC(C)C)CNC(=O)[C@H](CC(C)C)NC(=O)NC1=CC=C(Br)C=C1 SJBYUKPOGWWLGD-SFHVURJKSA-N 0.000 claims 1
- OHDBESLRXKFIOM-KRWDZBQOSA-N (2s)-2-[(4-bromophenyl)carbamoylamino]-n-[di(propan-2-yloxy)phosphorylmethyl]pentanamide Chemical compound CC(C)OP(=O)(OC(C)C)CNC(=O)[C@H](CCC)NC(=O)NC1=CC=C(Br)C=C1 OHDBESLRXKFIOM-KRWDZBQOSA-N 0.000 claims 1
- VUOXMFYDMVFHRT-JTQLQIEISA-N (2s)-2-[(4-bromophenyl)carbamoylamino]pentanoic acid Chemical compound CCC[C@@H](C(O)=O)NC(=O)NC1=CC=C(Br)C=C1 VUOXMFYDMVFHRT-JTQLQIEISA-N 0.000 claims 1
- HOKBBCNUVRWBED-NSHDSACASA-N (2s)-2-[(4-iodophenyl)carbamoylamino]-4-methylpentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)NC1=CC=C(I)C=C1 HOKBBCNUVRWBED-NSHDSACASA-N 0.000 claims 1
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- HILAEZFSMOFJEY-ROUUACIJSA-N (2s)-2-[[(2s)-2-[(4-bromophenyl)carbamoylamino]-4-methylpentanoyl]amino]-2-phenylacetic acid Chemical compound N([C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)C=1C=CC=CC=1)C(=O)NC1=CC=C(Br)C=C1 HILAEZFSMOFJEY-ROUUACIJSA-N 0.000 claims 1
- AMMVIGUFZGQAQO-GJZGRUSLSA-N (2s)-2-[[(2s)-2-[(4-bromophenyl)carbamoylamino]-4-methylpentanoyl]amino]-3-methylbutanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)NC1=CC=C(Br)C=C1 AMMVIGUFZGQAQO-GJZGRUSLSA-N 0.000 claims 1
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- YLBUEARKTSANET-GJZGRUSLSA-N (2s)-n-[(2s)-1-amino-3-methyl-1-oxobutan-2-yl]-2-[(4-bromophenyl)carbamoylamino]-4-methylpentanamide Chemical compound CC(C)[C@@H](C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)NC1=CC=C(Br)C=C1 YLBUEARKTSANET-GJZGRUSLSA-N 0.000 claims 1
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Classifications
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- C07C235/82—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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- C07D233/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Definitions
- the present invention relates to a method for treating ocular inflammatory diseases in a subject in need of such treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of Formyl peptide receptor 2 (FPR2).
- FPR2 Formyl peptide receptor 2
- the formyl peptide receptor (FPR) family is involved in host defense against pathogens, but also in sensing internal molecules that may provide signals of cellular dysfunction.
- This family includes 3 members in humans and one member of this family FPR2 (also known as FPRL-1 , ALXA4) is a G protein- coupled receptor that is expressed predominantly on inflammatory cells such as monocytes and neutrophils, as well as on T cells and has been shown to play a critical role in leukocyte trafficking during inflammation and human pathology (Chiang N, Serhan CN, Dahlen, S, Drazen JM, Hay DWP, Rovati E, Shimizu T, Yokomizo T, Brink, C.
- FPR2 is an exceptionally promiscuous receptor that responds to a large array of exogenous and endogenous ligands, including serum amyloid A (SAA), chemokine variant sCK38-1 , the neuroprotective peptide humanin, anti-inflammatory eicosanoid lipoxin A4 (LXA4) and glucocotricoid-modulated protein annexin A1 (Chiang N, Serhan CN, Dahlen, S, Drazen JM, Hay DWP, Rovati E, Shimizu T, Yokomizo T, Brink, C.
- SAA serum amyloid A
- LXA4 anti-inflammatory eicosanoid lipoxin A4
- glucocotricoid-modulated protein annexin A1 Choang N, Serhan CN, Dahlen, S, Drazen JM, Hay DWP, Rovati E, Shimizu T, Yokomizo T, Brink, C.
- the lipoxin receptor ALX Potent ligand-specific and stereoselective actions in vivo. Pharmacological Reviews 2006; 58: 463-519). FPR2 transduces anti-inflammatory effects of LXA4 in many systems, and has been shown to play a key role in the resolution of inflammation (Dufton N, Perretti M. Therapeutic anti-inflammatory potential of formyl peptide receptor agonists. Pharmacology & Therapeutics 2010; 127: 175-188).
- FPR2 knockout mice show exaggerated inflammation in disease conditions as expected by the biological role of the receptor (Dufton N, Hannon R, Brancaleone V, Dalli J, Patel HB, Gray M, D'Aquisto F, Buckingham JC, Perretti M, Flower RJ. Anti-inflammatory role of the murine formyl-peptide receptor 2: Ligand-specific effects on leukocyte responses and experimental inflammation. Journal of Immunology 2010; 184: 261 1 -2619).
- FPR2 Activation of FPR2 by lipoxin A4 or its analogs and by Annexin I protein has been shown to result in anti-inflammatory activity by promoting active resolution of inflammation which involves inhibition of polymorphonuclear neutrophils (PMNs) and eosinophils migration and also stimulate monocyte migration enabling clearance of apoptotic cells from the site of inflammation in a nonphlogistic manner (Maderna P, Cottell DC, Toivonen T, Philon N, Dalli J, Perretti M, Godson C. FPR2/ALX receptor expression and internalization are critical for lipoxin A4 and annexin-derived peptide-stimulated phagocytosis.
- PMNs polymorphonuclear neutrophils
- eosinophils migration also stimulate monocyte migration enabling clearance of apoptotic cells from the site of inflammation in a nonphlogistic manner
- FPR2/ALX receptor expression and internalization are critical for lipoxin A4 and annex
- FPR2 has been shown to inhibit NK cytotoxicity and promote activation of T cells which further contributes to down regulation of tissue damaging inflammatory signals.
- FPR2/ LXA4 interaction has been shown to be beneficial in experimental models of ischemia reperfusion, angiogenesis, ocular inflammation such as endotoxin-induced uveitis, and corneal wound healing (Serhan C. Resolution phase of
- FPR2 selectively would also have benefits of reduced side effects as compared to more broad acting anti-inflammatories such as steroids or NSAIDs which have significant side effects of elevated IOP and delays in wound healing in the eye.
- FPR2 is also expressed in ocular tissues in the cornea and also the posterior of eye, in addition to the inflammatory cells that migrate into the ocular tissues. FPR2 thus represents an important novel pro-resolutionary molecular target for the development of new therapeutic agents in ocular diseases with excessive inflammatory responses.
- the invention pertains to the ability of FPR2 agonists to exhibit ocular antiinflammatory activity with chemical stability and suitable for ocular delivery.
- FPR2 compounds show good potency at the receptor, a subset of compounds is exemplified in the tables below, and importantly, the FPR2 compounds are active topically, and therefore could be administered in many forms, including but not limited to eye drops.
- These compounds may also be administered directly or through a local drug delivery device applied to ocular tissue, and via IV, intramuscularly, intrathecally, subcutaneously, orally, intravitreally or intraperitoneal ⁇ .
- ocular inflammatory diseases including, but not limited to, uveitis, dry eye, keratitis, allergic eye disease, infectious keratitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, uveitis, retinitis, and choroiditis
- acute multifocal placoid pigment epitheliopathy Behcet's disease, post-surgical corneal wound healing, conditions caused by laser, conditions caused by photodynamic therapy, wet and dry age-related macular degeneration (ARMD), , conditions affecting the posterior part of the eye, such as maculopathies and retinal degeneration including non-exudative age related macular degeneration, exudative age related macular degeneration, choroidal neovascularization, diabetic retinopathy (proliferative), retinopathy of prematurity (ROP), acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular e
- ROP retinopathy of
- these compounds will be useful for the treatment of ocular inflammatory diseases associated with CNS disorders such as Alzheimer's disease, arthritis, sepsis, inflammatory bowel disease, cachexia, angina pectoris, rheumatoid arthritis and related inflammatory disorders, alopecia, systemic inflammatory diseases such as stroke, coronary artery disease, obstructive airway diseases, HIV-mediated retroviral infections, cardiovascular disorders including coronary artery disease, neuroinflammation, neurological disorders, pain and immunological disorders, asthma, allergic disorders, inflammation, systemic lupus erythematosus, ,.
- CNS disorders such as Alzheimer's disease, arthritis, sepsis, inflammatory bowel disease, cachexia, angina pectoris, rheumatoid arthritis and related inflammatory disorders, alopecia
- systemic inflammatory diseases such as stroke, coronary artery disease, obstructive airway diseases, HIV-mediated retroviral infections
- cardiovascular disorders including coronary artery disease, neuroinflammation, neurological disorders, pain
- Figure 1 FPR2 agonists show potent anti-inflammatory activity in endotoxin- induced uveitis model in rats.
- FIG. 1 FPR2 agonists show potent anti-inflammatory activity in endotoxin- induced uveitis model in rats.
- Figure 3 shows accelerated healing and re-epithelialization in a rabbit model of corneal wound as exemplified by Compound 3, ⁇ [(2S,3S)-2- ⁇ [(4- bromophenyl)carbamoyl]amino ⁇ -3-methylpentanoyl]amino ⁇ acetic acid.
- the present invention relates to a method for treating ocular inflammatory diseases in a subject in need of such treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of FPR2.
- the invention provides the use of at least one agonist of FPR2 for the manufacture of a medicament for the treatment of an ocular inflammatory disease or condition mediated by FPR2 in a mammal.
- the invention provides a method for treating ocular inflammatory diseases, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application S.N.13/668,835, provided that the compounds have binding activity at the FPR2 receptor.
- the invention provides the use of at least one compound as disclosed in U.S. patent application S.N.13/668,835 for the manufacture of a medicament for the treatment of an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor .
- the invention provides the use of at least one compound as disclosed in U.S. patent application S.N.13/668,835 for treating an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor .
- R 1 is sec-butyl, C 6 -io aryl, -CH 2 - (C 6 -io)aryl, -CH 2 -heterocycle, C -8 cycloalkyl
- R 2 is halogen or methyl
- R 3 is halogen
- R 4 is H, methyl or halogen
- R 5 is OR 6 or NH 2 ;
- R 6 is H or C 2-4 alkyl.
- the invention provides a method for treating ocular inflammatory diseases, which comprises administering a pharmaceutical composition, comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application S.N.13/523,579, provided that the compounds have binding activity at the FPR2 receptor.
- the invention provides the use of at least one compound as disclosed in U.S. patent application S.N. 13/523,579 for the manufacture of a medicament for the treatment of an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor. .
- the invention provides the use of at least one compound as disclosed in U.S. patent application S.N. 13/523,579 for treating an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.
- a 1 and b is 0;
- a 0 and b is 1 ;
- a is 1 and b is 1 ;
- R 1 is optionally substituted Ci -8 alkyl, optionally substituted C 3 -8 cycloalkyl, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C 6 -io aryl, optionally substituted C3-8 cycloalkenyl, - NR 11 R 12 or -OR 13 ;
- R 2 is optionally substituted Ci -8 alkyl or optionally substituted C 6 -io aryl;
- R 3 is hydrogen, optionally substituted Ci -8 alkyl, halogen, -COOR 15 , - OR 13 , -
- NR 11 R 12 , N0 2 optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C-6-10 aryl or optionally substituted C3-8 cycloalkenyl;
- R 4 is hydrogen, optionally substituted Ci -8 alkyl, halogen, - COOR 15 , - OR 13 , - NR 11 R 12 , N0 2 , optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C 6 -io aryl or optionally substituted C3-8 cycloalkenyl;
- R 5 is halogen, -CF 3 or -S(0) n R 14 ;
- n 0, 1 or 2;
- R 6 is hydrogen, optionally substituted Ci -8 alkyl, halogen, - COOR 15 , - OR 13 , - NR 11 R 12 , N0 2 , optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C 6 -io aryl or optionally substituted C3-8 cycloalkenyl;
- R 7 is hydrogen, optionally substituted Ci -8 alkyl, halogen, - COOR 15 , - OR 13 , - NR 11 R 12 , N0 2 , optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C 6 -io aryl or optionally substituted C3-8 cycloalkenyl;
- R 8 is hydrogen, optionally substituted Ci -8 alkyl or optionally substituted C 6 -io aryl;
- R 9 is hydrogen, optionally substituted Ci -8 alkyl or optionally substituted C 6 -io aryl;
- R 10 is hydrogen, optionally substituted Ci -8 alkyl or optionally substituted C 6 -io aryl;
- R 9a is hydrogen, optionally substituted Ci -8 alkyl or optionally substituted C6-10 aryl;
- R 10a is hydrogen, optionally substituted Ci -8 alkyl or optionally substituted C 6 -io aryl;
- R 11 is hydrogen or optionally substituted Ci -8 alkyl
- R 12 is hydrogen or optionally substituted Ci -8 alkyl
- R 13 is hydrogen or optionally substituted Ci -8 alkyl
- R 14 is hydrogen, CF 3 or optionally substituted Ci -8 alkyl
- R 15 is hydrogen or optionally substituted Ci -8 alkyl;
- the invention provides a method for treating ocular inflammatory diseases, which comprises administering a pharmaceutical composition, comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application S.N. 13/673,800, provided that the compounds have binding activity at the FPR2 receptor..
- the invention provides the use of at least a compound as disclosed in U.S. patent application S.N. 13/673,800 for the manufacture of a medicament for the treatment of an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.
- the invention provides the use of at least a compound as disclosed in U.S. patent application S.N. 13/673,800 for treating an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.
- R 1 is halogen, hydrogen, optionally substituted C -8 alkyl, OR 9 , C(0)R 10 , N0 2 , NR 13 R 14 , CN, SR 15 or S0 2 R 16 ;
- R 2 is halogen, optionally substituted C i -8 alkyl, CF 3 , OR 9 , C(0)R 10 , N0 2 , NR 13 R 14 , CN, SR 15 or S0 2 R 16 ;
- R is hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C 6 -io aryl, optionally substituted heterocycle, or together with R 5 forms a 10- or 1 1- membered polycyclic ring which is optionally sub , optionally substituted C
- R 5 is hydrogen, optionally substituted C i -8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C 6 -io aryl, optionally substituted heterocycle, or together with R 4 forms a spiro monocyclic or polycyclic, carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 member ring which is optionally substituted;
- R 5 is hydrogen, optionally substituted C i -8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C 6 -io aryl, optionally substituted heterocycle, or together with R 4 forms a spiro monocyclic or polycyclic carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 member ring which is optionally substituted or together with R 3 forms a 5 or 6 member ring which is optionally substituted;
- R 6 is halogen, hydrogen, optionally substituted C i -8 alkyl, OR 9 , C(0)R 10 , N0 2 , NR 13 R 14 , CN, SR 15 or S0 2 R 16 ;
- R 7 is halogen, hydrogen, optionally substituted C -8 alkyl, OR 9 , C(0)R 10 , N0 2 , NR 13 R 14 , CN, SR 15 or S0 2 R 16 ;
- R 8 is halogen, hydrogen, optionally substituted C i -8 alkyl, OR 9 , C(0)R 10 , N0 2 , NR 13 R 14 , CN, SR 15 or S0 2 R 16 ;
- R 9 is hydrogen, C(0)(Ci -8 alkyl) or optionally substituted C i -8 alkyl;
- R 10 is hydrogen, optionally substituted C i -8 alkyl, 0(C i -8 alkyl), NR 11 R 12 or OH;
- R 11 is hydrogen, optionally substituted C 6 -io aryl or optionally substituted C i -8 alkyl;
- R 12 is hydrogen, optionally substituted C 6 -io aryl or optionally substituted C i -8 alkyl;
- R 13 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C i -8 alkyl
- R 14 is hydrogen, optionally substituted C 6 -io aryl, optionally substituted C i -8 alkyl, C(0)(C i -8 alkyl) or S0 2 (C i -8 alkyl);
- R 15 is hydrogen, optionally substituted C i -8 alkyl or 0(C i -8 alkyl);
- R 16 is OH, 0(C 1-8 alkyl), (C i -8 alkyl) or NR 11 R 12 ;
- R 17 is hydrogen, optionally substituted C 6 -io aryl or optionally substituted C i -8 alkyl;
- R 18 is hydrogen, C(0)(Ci -8 alkyl), optionally substituted C 6 -io aryl, or optionally substituted C i -8 alkyl;
- R 19 is hydrogen, C(0)(Ci -8 alkyl), optionally substituted C 6 -io aryl or optionally substituted C i -8 alkyl;
- R 20 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C i -8 alkyl;
- R 21 is hydrogen, optionally substituted C 6 -io aryl or optionally substituted C i -8 alkyl;
- n 1 , 2, 3, 4, or 5;
- n 1 , 2, 3, 4, or 5.
- the invention provides a method for treating ocular inflammatory diseases, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application S.N. 13/765,527, provided that the compounds have binding activity at the FPR2 receptor.
- the invention provides the use of at least one compound as disclosed in U.S. patent application S.N. 13/765,527 for the manufacture of a medicament for the treatment of an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.
- the invention provides the use of at least one compound as disclosed in U.S. patent application S.N. 13/765,527 for treating an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.
- R 1 is hydrogen, halogen, substituted or unsubstituted Ci -6 alkyl, substituted or unsubstituted C 2 -6 alkenyl, substituted or unsubstituted C 2 -6 alkynyl, substituted or unsubstituted C 3 -8 cycloalkyl, substituted or unsubstituted C 3 -8 cycloalkenyl substituted or unsubstituted heterocycle or substituted or unsubstituted C 6 -io aryl, or together with R 2 can form an optionally substituted cyclobutyl;
- R 2 is isopropyl or together with R 3 can form a substituted or unsubstituted 3 to 6 member ring heterocycle or together with R 1 can form an optionally substituted cyclobutyl, cyclopropyl;
- R 3 is hydrogen, substituted or unsubstituted C -6 alkyl, substituted or
- the invention provides a method for treating ocular inflammatory diseases, which comprises administering a therapeutically effective amount of a pharmaceutical composition, comprising at least one agonist of FPR2 as disclosed in U.S. patent application S.N. 13/409,228, provided that the compounds have binding activity at the FPR2 receptor.
- the invention provides the use of at least one compound as disclosed in U.S. patent application S.N. 13/409,228 for the manufacture of a medicament for the treatment of an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.
- the invention provides the use of at least one compound as disclosed in U.S. patent application S.N. 13/409,228 for treating an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.
- R 1 is H, halogen, -S(0)R 10 , -S(0) 2 R 11 , nitro, cyano, -OCi -6 alkyl, -SCi- 6 alkyl, -Ci -6 alkyl, -C 2-6 alkenyl, - C 2 -6 alkynyl, C(0)R 12 , NR 13 R 14 , C 3 -s cycloalkyl, C 3 -8 cycloalkenyl or hydroxyl;
- R 2 is H, halogen, -S(0)R 10 , -S(0) 2 R 11 , nitro, cyano, -OCi -6 alkyl, -SC1-6 alkyl, -Ci -6 alkyl, -C 2-6 alkenyl, - C 2-6 alkynyl, C(0)R 12 , NR 13 R 14 , C 3 - 8 cycloalkyl, C3-8 cycloalkenyl or hydroxyl;
- R 3 is H, halogen, -S(0)R 10 , -S(0) 2 R 11 , nitro, cyano, -OCi -6 alkyl, -SCi- 6 alkyl, -Ci -6 alkyl, -C 2-6 alkenyl, - C 2-6 alkynyl, C(0)R 12 , NR 13 R 14 , C 3 - 8 cycloalkyl, C3-8 cycloalkenyl, C-6-10 aryl or hydroxyl;
- R 4 is H or C(0)R 12 ;
- R 5 is H , -OC1-6 alkyl, -SCi- 6 alkyl, -Ci- 6 alkyl, -C 2-6 alkenyl or - C 2-6 alkynyl;
- R 6 is H, -OC1-6 alkyl, -SCi- 6 alkyl, -Ci -6 alkyl, -C2-6 alkenyl or - C 2 -6 alkynyl;
- Y is O or S
- X is O, NR, or
- R a is C 6 -io aryl, heteroaryl, C3-8 cycloalkyl, C3-8 cycloalkenyl or H;
- R b is halogen
- c 0, 1 or 2;
- R 7 is H, halogen, -S(0)R 10 , -S(0) 2 R 1 1 , nitro, hydroxyl, cyano, -OCi -6 alkyl, -SCi -6 alkyl, -Ci -6 alkyl, -C 2 - 6 alkenyl, - C 2 - 6 alkynyl, C(0)R 12 , NR 13 R 14 , C 3 - 8 cycloalkenyl or C3-8 cycloalkyl;
- R 8 is H, halogen, -S(0)R 10 , -S(0) 2 R 1 1 , cyano, -OCi -6 alkyl, -SCi -6 alkyl, - C1-6 alkyl, -C 2-6 alkenyl, - C 2-6 alkynyl, C(0)R 12 , NR 13 R 14 , C 3 - 8 cycloalkenyl or C3-8 cycloalkyl;
- R 9 is H, -S(0) 2 R 11 , -OC1-6 alkyl, -SCi -6 alkyl, -Ci -6 alkyl, -C 2-6 alkenyl, - C 2- 6 alkynyl, C(0)R 12 , C3-8 cycloalkenyl or C3-8 cycloalkyl ;
- R 10 is -C1-6 alkyl, C3-8 cycloalkyl, or C3-8 cycloalkenyl ;
- R 11 is H, hydroxyl, -Ci -6 alkyl, C3-8 cycloalkyl or C3-8 cycloalkenyl;
- R 12 is H, hydroxyl, -Ci -6 alkyl, C 3 - 8 cycloalkyl, C 3 - 8 cycloalkenyl, NR 13 R 14 or -OC1-6 alkyl;
- R 13 is H, -C1-6 alkyl, C 3 -s cycloalkyl, C 3 -s cycloalkenyl S0 2 R 1 1 or C(0)R 15 ;
- R 14 is H, -C1-6 alkyl, C 3 -s cycloalkenyl, aryl, heterocycle or C 3 -s cycloalkyl;
- R 15 is H, -C1-6 alkyl, C 3 -s cycloalkenyl or C 3 -s cycloalkyl; and R is H, -Ci-6 alkyl, C 3 -8 cycloalkenyl or C3-8 cycloalkyl;
- the invention provides a method for treating ocular inflammatory diseases, which comprises administering a pharmaceutical composition, comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application S.N. 13/370,472, provided that the compounds have binding activity at the FPR2 receptor.
- the invention provides the use of at least one compound as disclosed in U.S. patent application S.N. 13/370,472 for the manufacture of a medicament for the treatment of an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.
- the invention provides the use of at least one compound as disclosed in U.S. patent application S.N. 13/370,472 for treating an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.
- A is C-6-10 aryl, heterocyle, C 3 -8 cycloalkyi or C 3 -8 cycloalkenyl;
- R 17 is Ci-6 alkyl or
- B is C-6-10 aryl, heterocyle, C 3 -8 cycloalkyi or C 3 -8 cycloalkenyl;
- R 1 is H, halogen, -S(0)R 15 , -S(0) 2 R 11 , nitro, cyano, -OCi -6 alkyl, -SCi -6 alkyl, - Ci-6 alkyl, -C 2 - 6 alkenyl, - C 2-6 alkynyl, C(0)R 12 , NR 13 R 14 , C 3-8 cycloalkyi or hydroxy I;
- R 2 is H, halogen, -S(0)R 15 , -S(0) 2 R 11 , nitro, cyano, -OCi -6 alkyl, -SCi -6 alkyl, - Ci-6 alkyl, -C 2-6 alkenyl, - C 2-6 alkynyl, C(0)R 12 , NR 13 R 14 , C 3-8 cycloalkyi or hydroxy I;
- R 3 is H, C-i-6 alkyl or C 3-8 cycloalkyi
- R 4 is H, Ci-6 alkyl or C 3- 8 cycloalkyi
- R 5a is H, halogen, -S(0)R 15 , -S(0) 2 R 11 , nitro, cyano, -OCi -6 alkyl, -SCi -6 alkyl, ⁇ Ci-6 alkyl, -C 2-6 alkenyl, - C 2-6 alkynyl, C(0)R 12 , NR 13 R 14 , C 3-8 cycloalkyi or hydroxy I;
- R 5b is H, halogen, -S(0)R 15 , -S(0) 2 R 11 , nitro, cyano, -OCi -6 alkyl, -SCi -6 alkyl, ⁇ Ci-6 alkyl, -C 2-6 alkenyl, - C 2-6 alkynyl, C(0)R 12 , NR 13 R 14 , C 3-8 cycloalkyi or hydroxy I;
- R 5c is H, halogen, -S(0)R 15 , -S(0) 2 R 11 , nitro, cyano, -OCi -6 alkyl, -SCi -6 alkyl, - Ci -6 alkyl, -C 2 - 6 alkenyl, - C 2 - 6 alkynyl, C(0)R 12 , NR 13 R 14 , C 3 - 8 cycloalkyl or hydroxy I;
- R 5d is H, halogen, -S(0)R 15 , -S(0) 2 R 11 , nitro, cyano, -OCi -6 alkyl, -SCi -6 alkyl, - C1-6 alkyl, -C 2 - 6 alkenyl, - C 2 - 6 alkynyl, C(0)R 12 , NR 13 R 14 , C 3 - 8 cycloalkyl or hydroxy I;
- R 6 is H, -S(0) 2 R 11 , -C1-6 alkyl, -(CH 2 ) n NR 13 R 14 , -(CH 2 ) m heterocycle , C(0)R 12 , NR 13 R 14 , C3-8 cycloalkyl, C6-10 aryl, or heterocycle;
- R 7 is H, halogen, -S(0)R 15 , -S(0) 2 R 11 , nitro, cyano, -OCi -6 alkyl, -SCi -6 alkyl, - C1-6 alkyl, -C 2-6 alkenyl, - C 2-6 alkynyl, C(0)R 12 , NR 13 R 14 , C 3 - 8 cycloalkyl or hydroxy I;
- R 8 is H, halogen, -S(0)R 15 , -S(0) 2 R 11 , nitro, cyano, -OCi -6 alkyl, -SCi -6 alkyl, - C1-6 alkyl, -C 2-6 alkenyl, - C 2-6 alkynyl, C(0)R 12 , NR 13 R 14 , C 3 - 8 cycloalkyl or hydroxy I;
- R 9 is H, halogen, -S(0)R 15 , -S(0) 2 R 11 , nitro, cyano, -OCi -6 alkyl, -SCi -6 alkyl, - C1-6 alkyl, -C 2-6 alkenyl, - C 2-6 alkynyl, C(0)R 12 , NR 13 R 14 , C 3 - 8 cycloalkyl or hydroxy I;
- R 10 is H, halogen, -S(0)R 15 , -S(0) 2 R 11 , nitro, cyano, -OCi -6 alkyl, -SCi -6 alkyl, - C1-6 alkyl, -C 2-6 alkenyl, - C 2-6 alkynyl, C(0)R 12 , NR 13 R 14 , C 3-8 cycloalkyl or hydroxy I;
- X is O or S
- Y is O or S
- R 11 is H, hydroxyl, -Ci -6 alkyl, C 3-8 cycloalkyl or NR 13 R 14 ;
- R 12 is H, hydroxyl, -Ci -6 alkyl, hydroxyl, C 3-8 cycloalkyl, NR 13 R 14 or -OCi -6 alkyl;
- R 13 is H, -C1-6 alkyl, C 3-8 cycloalkyl, S0 2 R 11 or C(0)R 16 ;
- R 14 is H, -C1-6 alkyl or C 3-8 cycloalkyl
- R 15 is -C1-6 alkyl, or C 3-8 cycloalkyl
- R 16 is H, -C1-6 alkyl or C 3-8 cycloalkyl
- n 1 -4;
- n 1 -4.
- the invention provides a method for treating ocular inflammatory diseases, which comprises administering a pharmaceutical composition, comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application S.N. 13/863,934, provided that the compounds have binding activity at the FPR2 receptor.
- the invention provides the use of at least one compound as disclosed in U.S. patent application S.N. 13/863,934 for the manufacture of a medicament for the treatment of an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.
- the invention provides the use of at least one compound as disclosed in U.S. patent application S.N. 13/863,934 for treating an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.
- n 0 or 1 ;
- R 1 is hydrogen, substituted or unsubstituted C-i-s alkyl, halogen, -NR 8 R 9 , - NC(0)R 20 , -OR 10 , -OC(0)R 21 -SR 11 , -C(0)R 12 , CN or N0 2 ;
- R 2 is hydrogen, substituted or unsubstituted d-s alkyl, halogen, - NR 8 R 9 , - NC(0)R 20 , -OR 10 , -OC(0)R 21 ' -SR 11 , -C(0)R 12 , CN or N0 2 ;
- R 3 is hydrogen, substituted or unsubstituted Ci -8 alkyl, halogen, - NR 8 R 9 , - NC(0)R 20 ' -OR 10 , -OC(0)R 21 , -SR 11 , -C(0)R 12 , CN, N0 2 , CF 3 , S(0)R 15 or S(0) 2 R 16 ;
- R 4 is hydrogen, substituted or unsubstituted Ci- 8 alkyl, halogen, - NR 8 R 9 , - NC(0)R 20 ⁇ -OR 10 , -OC(0)R 21 , -SR 11 , -C(0)R 12 , CN or N0 2 ;
- R 5 is hydrogen, substituted or unsubstituted Ci- 8 alkyl, halogen, - NR 8 R 9 , - NC(O)R 20 -OR 10 , -OC(0)R 21 , SR 11 , -C(0)R 12 , CN or N0 2 ;
- R 6 is hydrogen, substituted or unsubstituted Ci -8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 6 -io aryl, substituted or unsubstituted C 3-8 cycloalkenyl or -CH 2 R 19 ;
- R 7 is substituted or unsubstituted heterocycle, -SR 11 , -NR 8 R 9 , - N(H)C(0)N(H)S(0) 2 R 19 , -BR 13 R 14 , -S(0)R 15 , -C(0)N(H)(CN), - C(0)N(H)S(0) 2 R 19 , -S(0)(N)(P0 3 H 2 )-, -S(0) 2 R 16 or -P(0)R 17 R 18 ;
- R 8 is hydrogen, substituted or unsubstituted Ci- 8 alkyl substituted or
- R 9 is hydrogen, substituted or unsubstituted Ci- 8 alkyl substituted or
- R 10 is hydrogen or substituted or unsubstituted Ci- 8 alkyl ;
- R 11 is hydrogen , substituted or unsubstituted d- 8 alkyl or -CF 3 ;
- R 12 is hydrogen, substituted or unsubstituted d-s alkyl, hydroxyl, -OR 24 or -
- R 13 is -OR 22 ;
- R 14 is -OR 23 ;
- R 15 is substituted or unsubstituted d- 8 alkyl
- R 16 is substituted or unsubstituted Ci- 8 alkyl, -NR 8 R 9 , -NHS(0) 2 R 19 or hydroxyl;
- R 17 is OR 10 or NR 8 R 9 ;
- R 18 is OR 10 or NR 8 R 9 ;
- R 19 is substituted or unsubstituted heterocycle, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C 6 -io aryl or substituted or unsubstituted C3-8 cycloalkenyl;
- R 20 is hydrogen, substituted or unsubstituted d-s alkyl substituted or
- R 21 is hydrogen, substituted or unsubstituted d-s alkyl substituted or
- R 22 is hydrogen, substituted or unsubstituted d-s alkyl, or together with R 23 can form a cycle;
- R 23 is hydrogen, substituted or unsubstituted d-s alkyl, or together with R 22 can form a cycle;
- R 24 is hydrogen, substituted or unsubstituted d-s alkyl substituted or
- alkyl refers to saturated, monovalent or divalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 8 carbon atoms.
- One methylene (- CH 2 -) group, of the alkyl group can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group.
- Alkyl groups can have one or more chiral centers.
- Alkyl groups can be independently substituted by halogen atoms, hydroxyl groups, cycloalkyl groups, amino groups, heterocyclic groups, aryl groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, phosphoric acid groups, nitro groups, amide groups, sulfonamide groups.
- cycloalkyl refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cyclic hydrocarbon.
- Cycloalkyl groups can be monocyclic or polycyclic. Cycloalkyl can be independently substituted by halogen atoms, sulfonyl d- 8 alkyl groups, sulfoxide Ci -8 alkyl groups, sulfonamide groups, nitro groups, cyano groups, - OC-i-8 alkyl groups, -SC-i-s alkyl groups, -C-i-s alkyl groups, -C2-6 alkenyl groups, - C 2 -6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups.
- cycloalkenyl refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cycloalkyl having at least one double bond. Cycloalkenyl groups can be monocyclic or polycyclic.
- Cycloalkenyl groups can be independently substituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, -OC1-6 alkyl groups, -SCi -6 alkyl groups, -Ci -6 alkyl groups, -C 2 -6 alkenyl groups, - C 2 -6 alkynyl groups , ketone groups, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups.
- halogen refers to an atom of chlorine, bromine, fluorine, iodine.
- alkenyl refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one double bond.
- One methylene (-CH 2 -) group, of the alkenyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group.
- C 2 -6 alkenyl can be in the E or Z configuration.
- Alkenyl groups can be substituted by alkyl groups, as defined above or by halogen atoms.
- alkynyl refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one triple bond.
- One methylene (-CH 2 -) group, of the alkynyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group.
- Alkynyl groups can be substituted by alkyl groups, as defined above, or by halogen atoms.
- heterocycle refers to a 3 to 10 membered ring, which can be aromatic or non-aromatic, saturated or unsaturated, containing at least one heteroatom selected form oxygen, nitrogen, sulfur, or combinations of at least two thereof, interrupting the carbocyclic ring structure.
- Heterocycles can be monocyclic or polycyclic.
- Heterocyclic ring moieties can be substituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, -OCi -6 alkyl groups, -SCi -6 alkyl groups, -Ci -8 alkyl groups, -C 2 -6 alkenyl groups, - C 2 -6 alkynyl groups , ketone groups, alkylamino groups, amino groups, aryl groups, C 3 -8 cycloalkyl groups or hydroxyl groups.
- aryl refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms, by removal of one hydrogen atom.
- Aryl can be substituted by halogen atoms, sulfonyl Ci -6 alkyl groups, sulfoxide Ci -6 alkyl groups, sulfonamide groups, carboxcyclic acid groups, Ci -6 alkyl carboxylates (ester) groups, amide groups, nitro groups, cyano groups, -OCi -6 alkyl groups, -SCi -6 alkyl groups, -Ci -6 alkyl groups, -C 2-6 alkenyl groups, - C 2-6 alkynyl groups , ketone groups, aldehydes, alkylamino groups, amino groups, aryl groups, C 3 -8 cycloalkyl groups or hydroxyl groups.
- Aryls can be monocyclic or polycyclic.
- hydroxyl as used herein, represents a group of formula "-OH”.
- carbonyl as used herein, represents a group of formula "- C(O)-”.
- ketone represents an organic compound having a carbonyl group linked to a carbon atom such as -(CO)R x wherein R x can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
- amine as used herein, represents a group of formula "-NR x R y ",wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
- sulfonyl as used herein, represents a group of formula "-S0 2 " ".
- sulfate as used herein, represents a group of formula "-0- S(0) 2 -0-".
- nitro as used herein, represents a group of formula "-N0 2 ".
- cyano as used herein, represents a group of formula "-CN”.
- amide as used herein, represents a group of formula "-
- R and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
- sulfonamide represents a group of formula "- S(0) 2 NR x R y " wherein R and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
- sulfoxide as used herein, represents a group of formula "- S(O)-”.
- phosphonic acid as used herein, represents a group of formula "-P(0)(OH) 2 ".
- N represents a nitrogen atom
- agonists of FPR2 are compounds selected from Table
- JP 63232846 discloses the resolution of N-(p-bromophenylcarbamyl) derivatives ((2S)-2-( ⁇ [(4-bromophenyl)amino]carbonyl ⁇ amino)-3- phenylpropanoic acid, (2S,3S)-2-( ⁇ [(4-bromophenyl)amino]carbonyl ⁇ amino)-3- methylpentanoic acid, 2-( ⁇ [(4-bromophenyl)amino]carbonyl ⁇ amino)-3-(1 H-indol- 3-yl)propanoic acid, (2S)-2-( ⁇ [(4-bromophenyl)amino]carbonyl ⁇ amino)-3- methylbutanoic acid) on HPLC column with novel chromatographic chiral stationary phases.
- agonists of FPR2 are compounds selected from Table
- agonists of FPR2 are compounds selected from Table
- the compounds of Table 3 are available from Chemical Libraries such as Chemical Block Ltd.
- Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound of the invention.
- Therapeutic utilities of the FPR2 are ocular inflammatory diseases including, but not limited to, wet and dry age-related macular degeneration (ARMD), uveitis, dry eye, Keratitis, allergic eye disease and conditions affecting the posterior part of the eye, such as maculopathies and retinal degeneration including non-exudative age related macular degeneration, exudative age related macular degeneration, choroidal neovascularization, diabetic retinopathy (proliferative), retinopathy of prematurity (ROP), acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, and diabetic macular edema; infectious keratitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, uveitis, retinitis, and choroiditis such as acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, infectious
- FPR2 FPR2 vascular endothelial growth factor 2
- AMD age-related macular degeneration
- ROP retinopathy of prematurity
- diabetic macular edema uveitis
- dry eye dry eye
- retinal vein occlusion cystoids macular edema
- glaucoma dry eye
- PVR proliferative vitreoretinopathy
- methods for treating disorders associated with modulation of the FPRL-1 receptor can be performed, for example, by administering to a subject in need thereof a therapeutically effective amount of at least one compound of the invention, or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual isomers, enantiomers, and diastereisomers thereof.
- the actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient's general physical condition, the cause of the condition, and the route of administration.
- the patient will be administered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea.
- routes may include, without exception, transdermal, parenteral, subcutaneous, intranasal, via an implant stent, intrathecal, intravitreal, topical to the eye, back to the eye, intramuscular, intravenous, and intrarectal modes of delivery.
- the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy.
- compositions including at least one compound of the invention in a pharmaceutically acceptable carrier thereof.
- pharmaceutically acceptable means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a patch, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications.
- Invention compounds may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
- the carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form.
- Invention compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition.
- compositions containing invention compounds may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
- Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
- Tablets containing invention compounds in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods.
- the excipients used may be, for example, (1 ) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
- formulations for oral use may be in the form of hard gelatin capsules wherein the invention compounds are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the invention compounds are mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin.
- water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
- compositions containing invention compounds may be in a form suitable for topical use, for example, as oily suspensions, as solutions or suspensions in aqueous liquids or nonaqueous liquids, or as oil-in-water or water-in-oil liquid emulsions.
- compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, or a pharmaceutically acceptable salt thereof, as an active ingredient with conventional ophthalmically acceptable pharmaceutical excipients and by preparation of unit dosage suitable for topical ocular use.
- the therapeutically efficient amount typically is between about 0.001 and about 5% (w/v), preferably about 0.001 to about 2.0% (w/v) in liquid formulations.
- solutions are prepared using a
- physiological saline solution as a major vehicle.
- the pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential.
- the formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.
- Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate.
- a preferred surfactant is, for example, Tween 80.
- various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose cyclodextrin and purified water.
- Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
- buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
- an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated
- excipient components which may be included in the ophthalmic preparations are chelating agents.
- the preferred chelating agent is edentate disodium, although other chelating agents may also be used in place of or in conjunction with it.
- the ingredients are usually used in the following amounts:
- the actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
- the ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate application to the eye.
- Containers suitable for dropwise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution.
- One package may contain one or more unit doses.
- Especially preservative-free solutions are often formulated in non-resealable containers containing up to about ten, preferably up to about five units doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops.
- the volume of one drop usually is about 20-35 ⁇ .
- the pharmaceutical compositions may be in the form of a sterile injectable suspension.
- This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
- Sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
- compositions may be prepared by mixing the invention compounds with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
- a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
- the compounds and pharmaceutical compositions described herein are useful as medicaments in mammals, including humans, for treatment of diseases and/or alleviations of conditions which are responsive to treatment by agonists or functional antagonists of FPR2.
- methods for treating a disorder associated with modulation of FPR2. can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one invention compound.
- therapeutically effective amount means the amount of the pharmaceutical composition that will elicit the biological or medical response of a subject in need thereof that is being sought by the researcher, veterinarian, medical doctor or other clinician.
- the subject in need thereof is a mammal.
- the mammal is human.
- FPR2 agonists would be expected to have significant effects in many different types of ocular inflammation, but have been exemplified by demonstrating anti-inflammatory activity in endotoxin-induced uveitis in rats ( Figures 1 and 2). Anti-inflammatory activity in this model has been exemplified with the FPR2 agonists described in Table 4.
- FLIPR HEK-Ga16 cells stably expressing the human FPR2 receptor was utilized. Cells were plated into 384-well poly-D-lysine coated plates at a density of 18,000 cells per well one day prior to use. The growth media was DMEM medium supplemented with 10% fetal bovine serum (FBS), 1 % antibiotic- antimycotic, 50 ⁇ g/ml hygromycin, and 400 ⁇ g/ml geneticin. On the day of the experiment, the cells were washed twice with Hank's Balanced Salt Solution 5 supplemented with 20 mM HEPES (HBSS/hepes buffer).
- FBS fetal bovine serum
- HBSS/hepes buffer 20 mM HEPES
- the cells were then dye loaded with 2 ⁇ Fluo-4 diluted in the HBSS/Hepes buffer and incubated at 37°C for 40 minutes. Extracellular dye was removed by washing the cell plates four times prior to placing the plates in the FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices). Ligands were diluted in HBSS/Hepes buffer and 10 prepared in 384-well microplates. Data for Ca +2 responses were obtained in relative fluorescence units.
- Immunohistochemistrv Chromagenic DAB immunohistochemistry with 5 antibodies specific to FPR2 was used to determine localization in normal human, primate, and rat eyes. Anti-FPR2 antibody (Abeam) was used at a dilution of 1 :200 to detect FPR2 protein in all species.
- Endotoxin-induced uveitis in rats Uveitis is a harmful ocular 0 inflammatory condition in humans. Anterior uveitis is a recurrent inflammatory disease and may have potentially blinding consequence. The pathogenesis of the disease is poorly understood, and the antiinflammatory therapy used is non-specific and is associated with significant complications. Animal models are key to understanding the 5 disease and testing novel therapies. A single low dose of lipopolysaccaride (LPS) in the footpad induces anterior uveitis in rats. This model known as endotoxin-induced uveitis serves as a useful paradigm of human anterior uveitis. Male Lewis rats (260 ⁇ 25 grams) were purchased from Charles River Laboratory.
- Rats were footpad- 0 injected (hind left side) with 100 ⁇ of 1 mg/ml LPS (List Biological Labs) solution (in sterile 0.9% saline).
- Test compounds were formulated in the vehicle consisting of sodium phosphate, dibasic heptahydrate, salts, CMC and sterile water. Compounds were topically (0.1 -1 %) or subcutaneously (10mg/kg) dosed 2 hr after LPS. Animals were sacrificed at 24 hours following LPS injection. Aqueous humor was collected and analyzed to determine inflammatory cell counts and total protein concentrations.
- Corneal epithelium plays an important role in the maintenance of corneal function and integrity. Prolonged corneal epithelial defects causes corneal opacity, neovascularization, bacterial infection and visual loss. Corneal epithelial healing is a complex process involving inflammatory response to injury, cell proliferation and migration.
- FPR2 agonists show accelerated healing and re-epithelialization in mouse models of corneal wound as exemplified by compound ⁇ [(2S,3S)-2- ⁇ [(4- bromophenyl)carbamoyl]amino ⁇ -3-methylpentanoyl]amino ⁇ acetic acid in ( Figure 3).
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Abstract
Description
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Priority Applications (25)
Application Number | Priority Date | Filing Date | Title |
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CN201910497947.0A CN110279684B (en) | 2013-03-06 | 2014-03-04 | Use of formyl peptide receptor 2 agonists for the treatment of ocular inflammatory diseases |
KR1020157024036A KR102227201B1 (en) | 2013-03-06 | 2014-03-04 | Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases |
MX2015011593A MX364916B (en) | 2013-03-06 | 2014-03-04 | Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases. |
CA2898301A CA2898301C (en) | 2013-03-06 | 2014-03-04 | Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases |
NZ710173A NZ710173B2 (en) | 2013-03-06 | 2014-03-04 | Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases |
EP14712888.8A EP2964213B1 (en) | 2013-03-06 | 2014-03-04 | Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases |
EP20205401.1A EP3795148A1 (en) | 2013-03-06 | 2014-03-04 | Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases |
BR122017004254-8A BR122017004254B1 (en) | 2013-03-06 | 2014-03-04 | USE OF FORMIL PEPTIDE 2 RECEPTOR AGONISTS TO TREAT EYE INFLAMMATORY DISEASES |
ES14712888T ES2835825T3 (en) | 2013-03-06 | 2014-03-04 | Use of formylated peptide receptor 2 agonists to treat inflammatory eye diseases |
RU2015136774A RU2663911C2 (en) | 2013-03-06 | 2014-03-04 | Use of agonists of formyl peptide receptor 2 for treating inflammatory eye diseases |
CN201480012204.5A CN105007909B (en) | 2013-03-06 | 2014-03-04 | For treating the purposes of 2 agonist of formyl peptide receptor of ocular inflammatory disease |
BR112015021371-5A BR112015021371B1 (en) | 2013-03-06 | 2014-03-04 | USE OF FORMIL PEPTIDE 2 RECEPTOR AGONISTS TO TREAT EYE INFLAMMATORY DISEASES |
AU2014225992A AU2014225992B2 (en) | 2013-03-06 | 2014-03-04 | Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases |
JP2015561536A JP6196327B2 (en) | 2013-03-06 | 2014-03-04 | Use of formyl peptide receptor 2 agonists for the treatment of ocular inflammatory diseases |
KR1020207023766A KR102290134B1 (en) | 2013-03-06 | 2014-03-04 | Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases |
SG11201507113RA SG11201507113RA (en) | 2013-03-06 | 2014-03-04 | Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases |
PH12015501858A PH12015501858B1 (en) | 2013-03-06 | 2015-08-24 | Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases |
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