IP Library › Granted Patent US 9,187,525
Granted Patent B2
US 9,187,525 · App. 14/011,879 · Granted Nov 17, 2015

Methods of treating ophthalmic diseases using NPR-B agonists

Inventors: Mark R. Hellberg (Arlington, TX); Iok-Hou Pang (Grand Prairie, TX)
Assignee: Shire Orphan Therapies GmbH
C07K7/06C07K7/02
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Quick Facts
Patent No.
US 9,187,525
App. No.
14/011,879
Granted
Nov 17, 2015
Kind
B2
Abstract

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.

Claims (188)

1. A method for treating ophthalmic disease in a patient in need thereof, said method comprising administering to said patient a composition comprising a therapeutically effective amount of a compound, wherein the compound is of the sequence

Occ-Sni-Phe-nle-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 (SEQ ID NO:166);

Occ-ala-Phe-leu-Leu-Pro-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:180);

Occ-Sni-Phe-leu-Leu-Pro-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:181);

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:182);

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:183);

Occ-ala-Pcf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:184);

Occ-ala-Phe-nle-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:185);

Occ-ala-Phe-arg-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 (SEQ ID NO:187);

Occ-ala-Pcf-leu-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 (SEQ ID NO:190);

Occ-ala-Nmf-leu-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 (SEQ ID NO:192);

Occ-pro-Phe-leu-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 (SEQ ID NO:193);

Occ-pip-Phe-leu-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 (SEQ ID NO:194);

Occ-ala-Phe-lys-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:195);

Occ-ala-Phe-orn-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:196);

Occ-pip-Nmf-arg-Leu-Pro-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:201);

Occ-pip-Phe-arg-Leu-Pro-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:202);

Occ-ala-Nmf-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:203);

Occ-ala-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:204);

Occ-pip-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:205);

Occ-ala-Pbf-arg-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 (SEQ ID NO:208);

Occ-ala-Phe-arg-Leu-Hyp-Npg-Asp-Arg-Ile-NH 2 (SEQ ID NO:217);

Occ-ala-Phe-Gly-Leu-Tap-Leu-Asp-Arg-Ile-NH 2 (SEQ ID NO:237);

Occ-ala-Phe-arg-Leu-Tap-Leu-Asp-Arg-Ile-NH 2 (SEQ ID NO:238);

Occ-ala-Phe-leu-Leu-Tap-Asp-Arg-Ile-NH 2 (SEQ ID NO:239);

Occ-ala-Phe-ser-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:240);

Occ-Sni-Phe-lys-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:242);

Occ-Sni-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:243);

Occ-Sni-Phe-orn-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:252);

Occ-ala-Nmf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:254);

Occ-ala-Phe-leu-Leu-Hyp-(SH-158)-Asp-Arg-Ile-NH 2 (SEQ ID NO:265);

Occ-ala-Phe-arg-Leu-Hyp-(SH-158)-Asp-Arg-Ile-NH 2 (SEQ ID NO:266);

Occ-Sni-Phe-dap(Me2)-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:267);

Occ-ala-Phe-orn(Me2)-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:268);

(AR-201-49)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:273);

Occ-Sni-Phe-leu-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:274);

Occ-ala-Phe-leu-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:275);

Oct-Sni-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:276);

Oct-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:278);

Occ-ala-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Tbg-NH 2 (SEQ ID NO:279);

Occ-Sni-Phe-arg-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:284);

Occ-Sni-Phe-orn-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:285);

Occ-Sni-Phe-Gly-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:287);

Occ-Sni-Phe-leu-Leu-Tap(G)-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:289);

Occ-Sni-Phe-leu-Leu-Tap(Bal)-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:290);

Occ-Sni-Phe-dap(Me2)-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:292);

Oct-Sni-Phe-leu-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:293);

Occ-ala-Phe-leu-Leu-Hyp-Nml-Val-Arg-Ile-NH 2 (SEQ ID NO:299);

Occ-ala-Phe-Fhy-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:304);

Occ-ala-Phe-Apc-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:306);

Occ-Sni-Phe-leu-Leu-Tap(Et)-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:317);

Occ-ala-Phe-Apc-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:318);

Occ-Sni-Phe-Apc-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:319);

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Tbg-NH 2 (SEQ ID NO:320);

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Egz-NH 2 (SEQ ID NO:321);

Occ-ala-Phe-leu-Leu-Hyp-Dap(Me2)-Asp-Arg-Ile-NH 2 (SEQ ID NO:330);

Oct-Sni-Phe-dap(Me2)-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:332);

Occ-Sni-Phe-leu-Leu-Tap(Ae)-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:334);

Occ-Sni-Phe-leu-Leu-Tap(Ap)-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:335);

(AR-201-68)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:343);

Sbt-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:345);

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Val-Arg-Ile-NH 2 (SEQ ID NO:353);

Occ-Sni-Phe-leu-Leu-Tap-Nml-Val-Arg-Ile-NH 2 (SEQ ID NO:356);

Occ-Sni-Phe-dap(Me2)-Leu-Tap-Nml-Val-Arg-Ile-NH 2 (SEQ ID NO:358);

Oct-Sni-Phe-dap(Me2)-Leu-Tap-Nml-Val-Arg-Ile-NH 2 (SEQ ID NO:360);

Occ-ala-Phe-Apc(Me)-Met-glu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:361);

Occ-ala-Phe-Apc(Et)-Glu-thr-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:362);

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Aml-NH 2 (SEQ ID NO:365);

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Deg-NH 2 (SEQ ID NO:366);

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Nmr-Ile-NH 2 (SEQ ID NO:367);

Oct-Sni-Phe-dap(Me2)-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:372);

Miy-Hgl-ala-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:373);

Occ-ala-Phe-Apc-Leu-Tap-Nml-Asp-Pro-Ile-NH 2 (SEQ ID NO:386);

Occ-ala-Phe-dap(Me2)-Leu-Tap-Nml-Asp-Pro-Ile-NH 2 (SEQ ID NO:387);

Occ-ala-Phe-Egz-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:388);

Occ-ala-Phe-dap(1464)-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:396);

Occ-Sni-Pff-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:406);

Occ-Sni-Pcf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:412);

Occ-Sni-Pmf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:413);

Occ-Sni-Eaa-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:414);

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Pro-1860 (SEQ ID NO:419);

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Pro-Che (SEQ ID NO:421);

Occ-Sni-Phe-Apc-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:425);

Occ-ala-Phe-leu-Leu-Hyp-Nml-(BB725)-Arg-Ile-NH 2 (SEQ ID NO:426);

Occ-ala-Phe-leu-Leu-Hyp-Nml-(BB727)-Arg-Ile-NH 2 (SEQ ID NO:428);

Occ-Sni-Phe-leu-Leu-Tap-Nml-Asp-Pro-Ile-NH 2 (SEQ ID NO:429);

Occ-Sni-Phe-Apc-Leu-Tap-Nml-Asp-Pro-Ile-NH 2 (SEQ ID NO:431);

Occ-Sni-Phe-leu-Leu-Tap-Nml-Asp-Pro-Che (SEQ ID NO:432);

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Nmi-NH 2 (SEQ ID NO:433);

Occ-Sni-Nmf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:436);

Occ-Sni-Phe-dap(Me2)-Leu-Hyp-Nml-Asp-Nmr-Ile-NH 2 (SEQ ID NO:439);

Occ-Sni-Nmf-dap(Me2)-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:442);

Occ-Sni-Phe-dap(Me2)-Leu-Hyp-Nml-Asp-Pro-Ile-NH 2 (SEQ ID NO:443);

Occ-Sni-Phe-leu-Leu-Hyp-Npg-Asp-Pro-Che (SEQ ID NO:445);

Occ-Sni-Nmf-leu-Leu-Hyp-Nml-Asp-Pro-Che (SEQ ID NO:447);

Occ-Sni-Eaa-leu-Leu-Hyp-Nml-Asp-Pro-Che (SEQ ID NO:449);

Occ-Sni-Phe-Apc-Leu-Tap-Nml-Asp-Pro-Che (SEQ ID NO:452);

Occ-Sni-Phe-dap(Me2)-Leu-Tap-Nml-Asp-Pro-Che (SEQ ID NO:453);

Occ-Sni-Phe-dap(Me2)-Leu-Hyp-Nml-Asp-Pro-Che (SEQ ID NO:454);

1319-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:455);

1320-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:456);

Occ-Sni-Mcf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:463);

Occ-Sni-Pbf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:464);

Occ-Sni-Thk-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:465);

Occ-Sni-Mtf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:466);

Occ-Sni-Phe-ctb-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:468);

Occ-Sni-Phe-leu-Nle-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:469);

Occ-Sni-Phe-leu-Leu-Hyp-Ile-Asp-Arg-Ile-NH 2 (SEQ ID NO:470);

Occ-Sni-Phe-leu-Leu-Hyp-Cpg-Asp-Arg-Ile-NH 2 (SEQ ID NO:471);

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Eaz-Che (SEQ ID NO:477);

Occ-Sni-Phe-leu-Leu-Tap-Nml-Val-Pro-Che (SEQ ID NO:481);

Occ-Sni-Phe-leu-Nle-Hyp-Nml-Asp-Pro-Che (SEQ ID NO:482);

5587-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:488);

Occ-(AFL)-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:491);

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Pca-Che (SEQ ID NO:495);

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Che (SEQ ID NO:496);

Occ-Sni-Phe-leu-Leu-Tap(Ae)-Nml-Asp-Arg-Che (SEQ ID NO:497);

Occ-Sni-Phe-leu-Leu-Tap-Nml-Asp-Arg-Che (SEQ ID NO:498);

Occ-Sni-Phe-leu-Leu-Tap-Nml-Val-Arg-Che (SEQ ID NO:506);

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Val-Arg-Che (SEQ ID NO:507);

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Ser-Arg-Che (SEQ ID NO:510);

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Thr-Arg-Che (SEQ ID NO:511);

(AR-314-87)-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:516);

(AR-314-102)-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:517);

Occ-Sni-Phe-orn(Me2)-Leu-Hyp-Nml-Asp-Arg-Che (SEQ ID NO:518);

Occ-Sni-Phe-lys(Me2)-Leu-Hyp-Nml-Asp-Arg-Che (SEQ ID NO:519);

Occ-Sni-Phe-lys(Me2)-Leu-Hyp-Nml-Val-Arg-Che (SEQ ID NO:521);

Occ-Sni-Phe-orn(Me2)-Leu-Hyp-Nml-Val-Arg-Ile-NH 2 (SEQ ID NO:523);

Occ-Sni-Phe-dab(Me2)-Leu-Hyp-Nml-Val-Arg-Che (SEQ ID NO:525);

Occ-Sni-Phe-dab(Me2)-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:526);

H-Adx-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:538);

Oct-Sni-Phe-leu-Leu-Tap-Nml-Asp-Arg-Che (SEQ ID NO:541);

Occ-Sni-Phe-orn(Me2)-Leu-Tap-Nml-Val-Arg-Che (SEQ ID NO:548);

Occ-Sni-Phe-(AR-385-12)-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:559);

Occ-Sni-Phe-Egg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:572);

Occ-Sni-Phe-orn(Me2)-Leu-Hyp-Nml-Thr-Arg-Che (SEQ ID NO:576);

H-Lys-Pro-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:581);

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Thr-Arg-Ile-NH 2 (SEQ ID NO:601); or

Occ-Sni-Phe-orn(Me2)-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:603).

2. A method for treating ophthalmic disease in a patient in need thereof, said method comprising administering to said patient a composition comprising a therapeutically effective amount of a compound, wherein the compound is of the sequence

Occ-ala-ala-Phe-Gly-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 (SEQ ID NO:81);

Occ-pro-Phe-Gly-Leu-Pro-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:127);

Occ-Sni-Nmf-Gly-Leu-Pro-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:130);

Occ-Sni-Nmf-Gly-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 (SEQ ID NO:135);

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:182);

Occ-ala-Nmf-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:203);

Occ-ala-Phe-arg-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 (SEQ ID NO:187);

Occ-ala-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:204);

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:183);

Occ-ala-Phe-lys-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:195);

Occ-Sni-Phe-dap(Me2)-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:267);

Occ-Sni-Phe-leu-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:274);

Occ-Sni-Phe-dap(Me2)-Leu-Hyp-Nml-Val-Arg-Ile-NH 2 (SEQ ID NO:355);

Occ-Sni-Phe-dap(Me2)-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:292);

Oct-Sni-Phe-dap(Me2)-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:332);

Oct-Sni-Phe-dap(Me2)-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:372);

Occ-Sni-Eaa-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:414);

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Pro-Che (SEQ ID NO:421);

Occ-Sni-Phe-Apc-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:425);

Occ-Sni-Phe-leu-Leu-Tap-Nml-Val-Pro-Che (SEQ ID NO:481);

Occ-Sni-Phe-leu-Leu-Tap-Nml-Val-Arg-Che (SEQ ID NO:506); or

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Val-Arg-Che (SEQ ID NO:507).

3. The method of claim 2 , wherein the compound is

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:182).

4. The method of claim 2 , wherein the compound is

Occ-ala-Nmf-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:203).

5. The method of claim 2 , wherein the compound is

Occ-ala-Phe-arg-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 (SEQ ID NO:187).

6. The method of claim 2 , wherein the compound is

Occ-ala-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:204).

7. The method of claim 2 , wherein the compound is

Occ-ala-Phe-lys-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:195).

8. The method of claim 2 , wherein the compound is

Occ-Sni-Phe-dap(Me2)-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:267).

9. The method of claim 2 , wherein the compound is

Occ-Sni-Phe-leu-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:274).

10. The method of claim 2 , wherein the compound is

Occ-Sni-Phe-dap(Me2)-Leu-Hyp-Nml-Val-Arg-Ile-NH 2 (SEQ ID NO:355).

11. The method of claim 1 , wherein said ophthalmic disease is glaucoma, elevated intraocular pressure, or ocular hypertension.

12. The method of claim 2 , wherein said ophthalmic disease is glaucoma, elevated intraocular pressure, or ocular hypertension.

13. The method of claim 3 , wherein said ophthalmic disease is glaucoma, elevated intraocular pressure, or ocular hypertension.

14. The method of claim 4 , wherein said ophthalmic disease is glaucoma, elevated intraocular pressure, or ocular hypertension.

15. The method of claim 5 , wherein said ophthalmic disease is glaucoma, elevated intraocular pressure, or ocular hypertension.

16. The method of claim 6 , wherein said ophthalmic disease is glaucoma, elevated intraocular pressure, or ocular hypertension.

17. The method of claim 7 , wherein said ophthalmic disease is glaucoma, elevated intraocular pressure, or ocular hypertension.

18. The method of claim 8 , wherein said ophthalmic disease is glaucoma, elevated intraocular pressure, or ocular hypertension.

19. The method of claim 9 , wherein said ophthalmic disease is glaucoma, elevated intraocular pressure, or ocular hypertension.

20. The method of claim 10 , wherein said ophthalmic disease is glaucoma, elevated intraocular pressure, or ocular hypertension.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 1, 2021
From: SHIRE ORPHAN THERAPIES GMBH
To: TAKEDA PHARMACEUTICAL COMPANY LIMITED
Reel/Frame 055105/0363 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 29, 2015
From: HELLBERG, MARK R.; PANG, IOK-HOU
To: ALCON RESEARCH, LTD.
Reel/Frame 034844/0796 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 6, 2014
From: ALCON RESEARCH, LTD.
To: SHIRE ORPHAN THERAPIES GMBH
Reel/Frame 033475/0125 →
Continuity (3)
Division 12888574 · Sep 23, 2010
Provisional Application 61287773 · Dec 18, 2009
Related Publication 20130345136A1 · Dec 26, 2013