Methods of treating ophthalmic diseases using NPR-B agonists
Disclosed are novel compounds having NPR-B agonistic activity. Preferred compounds are linear peptides containing 8-13 conventional or non-conventional L- or D-amino acid residues connected to one another via peptide bonds.
1. A method for treating ophthalmic disease in a patient in need thereof, said method comprising administering to said patient a therapeutically effective amount of a compound having the following formula:
wherein
B is selected from the group consisting of R b1 — and R b2 —C(O)—, wherein:
R b1 is selected from the group consisting of C 6 -C 10 alkyl and C 6 -C 10 alkyl substituted by NR b4 R b5 ;
R b2 is C 6 -C 10 alkyl substituted by NR b4 R b5 ; and
R b4 and R b5 are, independently, selected from the group consisting of H and C 1 -C 4 alkyl; and
R 11b is selected from the group consisting of H, C 1 -C 8 alkyl, C 4 -C 8 cycloalkyl, C 7 -C 12 bicycloalkyl, and C 1 -C 4 alkyl-C 4 -C 8 cycloalkyl.
2. The method of claim 1 , wherein:
R 11b is selected from the group consisting of H and C 1 -C 8 alkyl.
3. The method of claim 1 , wherein said ophthalmic disease is glaucoma, elevated intraocular pressure, or ocular hypertension.
4. A method for treating ophthalmic disease in a patient in need thereof, said method comprising administering to said patient a therapeutically effective amount of a compound having the following formula:
wherein
B is selected from the group consisting of R b1 — and R b2 —C(O)—, wherein:
R b1 is selected from the group consisting of C 6 -C 10 alkyl and C 6 -C 10 alkyl substituted by NR b4 R b5 ;
R b2 is C 6 -C 10 alkyl substituted by NR b4 R b5 ; and
R b4 and R b5 are, independently, selected from the group consisting of H and C 1 -C 4 alkyl; and
R 11b is selected from the group consisting of H, C 1 -C 8 alkyl, C 4 -C 8 cycloalkyl, C 7 -C 12 bicycloalkyl, and C 1 -C 4 alkyl-C 4 -C 8 cycloalkyl.
5. The method of claim 4 , wherein:
R 11b is selected from the group consisting of H and C 1 -C 8 alkyl.
6. The method of claim 4 , wherein said ophthalmic disease is glaucoma, elevated intraocular pressure, or ocular hypertension.
7. A method for treating ophthalmic disease in a patient in need thereof, said method comprising administering to said patient a therapeutically effective amount of a compound selected from:
(SEQ ID NO: 228)
6054-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 244)
Occ-Sni-Mpa-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 245)
Occ-Sni-Ppa-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 246)
(6071-OH)-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 248)
5587-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 270)
(AR-201-48)-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 272)
(AR-201-48)-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 307)
(AR-201-58)-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 308)
(AR-201-59)-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 311)
Sbt-Sni-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 313)
Sbt-ala-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 314)
Nbt-ala-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 339)
(AR-201-72)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 340)
(AR-201-72)-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 374)
Miy-Gab-Hgl-ala-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-
NH2;
(SEQ ID NO: 375)
Ac-Miy-Gab-Hgl-ala-Phe-arg-Leu-Hyp-Nml-Asp-Arg-
Ile-NH2;
(SEQ ID NO: 408)
Occ-Sni-Tyr-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 409)
Occ-Sni-Bmf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 423)
Occ-Sni-Phe-Ala-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 437)
Occ-Sni-Phe-nml-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 457)
2553-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 460)
6988-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 462)
1695-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 467)
Occ-Sni-Otf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 474)
Occ-Sni-NHfe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 484)
785-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 486)
3218-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 489)
1281-G-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 490)
1281-Bal-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 504)
Occ-Sni-Hfe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 505)
Occ-ala-Nmf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 533)
Gluc-Aoa-hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-
NH2;
(SEQ ID NO: 535)
(1270)-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 537)
Occ-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 555)
(AR-314-170)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 556)
(AR-314-171)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2;
(SEQ ID NO: 557)
(AR-385-008)-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH2; and
(SEQ ID NO: 565)
Occ-Sni-Phe-thr-Leu-Hyp-Nml-Asp-Arg-Ile-NH2.
8. The method of claim 7 , wherein said ophthalmic disease is glaucoma, elevated intraocular pressure, or ocular hypertension.
9. The method of claim 7 , wherein the compound is selected from:
(SEQ ID NO: 457)
2553-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;
(SEQ ID NO: 460)
6988-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;
(SEQ ID NO: 462)
1695-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;
(SEQ ID NO: 484)
785-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;
(SEQ ID NO: 486)
3218-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;
(SEQ ID NO: 489)
1281-G-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;
(SEQ ID NO: 490)
1281-Bal-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;
(SEQ ID NO: 533)
Gluc-Aoa-hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-
NH 2 ;
(SEQ ID NO: 535)
(1270)-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-
NH 2 ; and
(SEQ ID NO: 537)
Occ-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 .
10. The method of claim 9 , wherein said ophthalmic disease is glaucoma, elevated intraocular pressure, or ocular hypertension.