IP Library › Granted Patent US 9,169,293

Granted Patent B2

US 9,169,293 · App. 14/011,855 · Granted Oct 27, 2015

NPR-B agonists

Inventors: Frank Osterkamp (Berlin, DE); Heiko Hawlisch (Berlin, DE); Gerd Hummel (Berlin, DE); Tobias Knaute (Berlin, DE); Ulf Reimer (Berlin, DE); Ulrich Reineke (Berlin, DE); Bernadett Simon (Bonn, DE); Uwe Richter (Berlin, DE); Edgar Specker (Berlin, DE); Markus Woischnik (Berlin, DE); Mark R. Hellberg (Arlington, TX)

Assignee: Shire Orphan Thereapies GmbH

C07K7/08 C07K7/02 C07K7/06

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Quick Facts

Patent No.: US 9,169,293
App. No.: 14/011,855
Granted: Oct 27, 2015
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

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 (537)

1. A compound of the sequence:

(SEQ ID NO: 22)

Hex-Ala-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-

Ala-NH 2 ;

(SEQ ID NO: 24)

Hex-Gly-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-

Ala-NH 2 ;

(SEQ ID NO: 25)

Hex-Gly-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-

Gly-NH 2 ;

(SEQ ID NO: 52)

Occ-Nip-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 53)

Occ-ala-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 62)

Occ-Sni-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 68)

Occ-ala-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-2797;

(SEQ ID NO: 86)

Occ-ala-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-1860;

(SEQ ID NO: 90)

Occ-ala-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Che;

(SEQ ID NO: 92)

Occ-ala-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-1934;

(SEQ ID NO: 93)

Occ-ala-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-1906;

(SEQ ID NO: 96)

Occ-ala-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-5119;

(SEQ ID NO: 103)

Occ-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-1860;

(SEQ ID NO: 107)

Occ-ala-Phe-Gly-Leu-Pro-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 109)

Occ-ala-Phe-Gly-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 125)

Occ-aze-Phe-Gly-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 126)

Occ-ala-Nmf-Gly-Leu-Pro-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 128)

Occ-Sni-Phe-Gly-Leu-Pro-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 136)

Occ-ala-Phe-Gly-Leu-Apr-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 153)

Occ-ala-Phe-ser-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 154)

Occ-ala-Phe-thr-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 156)

Occ-ala-Phe-leu-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 157)

Occ-ala-Phe-nle-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 158)

Occ-Sni-Phe-Gly-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 159)

Occ-ala-Phe-Gly-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 160)

Occ-ala-Phe-asn-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 161)

Occ-ala-Phe-met-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 162)

Occ-ala-Phe-abu-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 163)

Occ-ala-Phe-dap-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 164)

Occ-Sni-Phe-nle-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 165)

Occ-Sni-Nmf-nle-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 167)

Occ-ala-Phe-nle-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 168)

Occ-ala-Phe-leu-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 169)

Occ-ala-Phe-nva-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 170)

Occ-ala-Phe-phe-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 171)

Occ-ala-Phe-ctb-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 172)

Occ-ala-Phe-lys-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 173)

Occ-ala-Phe-arg-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 174)

Occ-ala-Phe-his-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 175)

Ac-Hgl-ala-ala-Phe-Gly-Leu-Pro-Leu-Asp-Arg-Ile-

NH 2 ;

(SEQ ID NO: 176)

Ac-hgl-ala-ala-Phe-Gly-Leu-Pro-Leu-Asp-Arg-Ile-

NH 2 ;

(SEQ ID NO: 191)

Occ-ala-Pmf-leu-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 197)

Occ-ala-Phe-lys-Leu-Pro-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 199)

Occ-ala-Phe-arg-Leu-Pro-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 200)

Occ-ala-Nmf-arg-Leu-Pro-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 206)

Occ-ala-Phe-arg-Leu-Tfp-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 207)

Occ-ala-Phe-Gly-Leu-Tfp-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 209)

Occ-ala-Phe-dab-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 210)

Occ-ala-Phe-nar-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 211)

Occ-ala-Phe-gdp-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 212)

Oct-ala-Phe-arg-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 215)

832-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 216)

Occ-ala-Phe-arg-Leu-Hyp-Ile-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 219)

Occ-ala-Phe-arg-Leu-Hyp-Ebe-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 220)

Occ-ala-Phe-arg-Leu-Lys-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 221)

Occ-ala-Phe-arg-Leu-Nmk-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 223)

Occ-ala-Phe-arg-Leu-Sar-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 224)

Occ-ala-Phe-arg-Nva-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 225)

cc-ala-Phe-arg-Ebe-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 226)

6014-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 227)

6015-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 229)

6056-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 230)

6057-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 231)

6058-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 232)

6059-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 233)

832-Nmf-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 234)

832-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 235)

832-Phe-arg-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 241)

Occ-Sni-Phe-ser-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 247)

6072-OH)-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 249)

Occ-ala-Phe-Gly-Leu-Tap(2Me)-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 250)

Occ-ala-Phe-arg-Leu-Tap(2Me)-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 251)

Occ-ala-Phe-leu-Leu-Tap(2Me)-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 253)

Occ-Sni-Opa-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 254)

Occ-ala-Nmf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 255)

Occ-ala-Nmf-lys-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 256)

Occ-ala-Nmf-orn-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 257)

Occ-ala-Phe-Gly-Leu-Gup-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 258)

Occ-ala-Phe-arg-Leu-Gup-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 259)

Occ-ala-Phe-leu-Leu-Gup-Leu-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 260)

Oct-Sar-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 261)

Oct-aze-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 262)

Oct-Az3-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 263)

Occ-ala-Phe-leu-Leu-Eal-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 271)

(AR-201-49)-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 277)

6182-ala-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 280)

Occ-ala-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Eca-NH 2 ;

(SEQ ID NO: 281)

Occ-ala-Phe-arg-Leu-Hyp-Dap(Me2)-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 283)

(AR-201-54)-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 286)

Occ-Sni-Phe-nle-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 288)

Occ-Sni-Phe-leu-Leu-Tap(Ac)-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 291)

6059(O)-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 294)

Occ-ala-Phe-arg-Leu-Hyp-Nml-Asp-Orn-Ile-NH 2 ;

(SEQ ID NO: 295)

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Orn-Ile-NH 2 ;

(SEQ ID NO: 297)

Occ-ala-Phe-leu-Leu-Hyp-Nml-Glu-Arg-Ile-NH 2 ;

(SEQ ID NO: 298)

Occ-ala-Phe-arg-Leu-Hyp-Nml-Val-Arg-Ile-NH 2 ;

(SEQ ID NO: 300)

Occ-ala-Phe-leu-Leu-Hyp-Nml-Val-Arg-Ile-NH 2 ;

(SEQ ID NO: 301)

Occ-ala-Phe-arg-Leu-Hyp-Nml-Thr-Arg-Ile-NH 2 ;

(SEQ ID NO: 302)

Occ-ala-Phe-leu-Leu-Hyp-Nml-Thr-Arg-Ile-NH 2 ;

(SEQ ID NO: 303)

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Eca-NH 2 ;

(SEQ ID NO: 305)

Occ-ala-Phe-Egg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 309)

(AR-201-62)-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 310)

(AR-201-69)-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 312)

Nbt-Sni-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 315)

Occ-ala-Phe-dap(Me2)-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 316)

Occ-Sni-Phe-leu-Leu-Tap(Et2)-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 322)

Occ-ala-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Egz-NH 2 ;

(SEQ ID NO: 326)

Occ-ala-Phe-leu-Leu-Hyp-Nml-Ile-Arg-Ile-NH 2 ;

(SEQ ID NO: 327)

Occ-ala-Phe-arg-Leu-Hyp-Oic-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 329)

Occ-ala-Phe-leu-Leu-Hyp-Pip-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 331)

Occ-ala-Phe-leu-Dap(Me2)-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 333)

Occ-Sni-Phe-dap(6263)2-Leu-Tap-Nml-Asp-Arg-

Ile-NH 2 ;

(SEQ ID NO: 336)

(AR-201-58)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 337)

(AR-201-62)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 338)

(AR-201-69)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 341)

(AR-201-73)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 342)

(AR-201-73)-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 344)

(AR-201-68)-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 346)

Nbt-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 347)

Occ-ala-Phe-leu-Leu-Hyp-Oic-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 352)

Occ-ala-Phe-arg-Leu-Hyp-Tic-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 354)

Oct-Sni-Phe-leu-Leu-Hyp-Nml-Val-Arg-Ile-NH 2 ;

(SEQ ID NO: 357)

Oct-Sni-Phe-dap(Me2)-Leu-Hyp-Nml-Val-Arg-Ile-NH 2 ;

(SEQ ID NO: 359)

Oct-Sni-Phe-leu-Leu-Tap-Nml-Val-Arg-Ile-NH 2 ;

(SEQ ID NO: 363)

Occ-ala-Phe-Apc(Ae)-Ala-glu--Leu-Hyp-Nml-Asp-Arg-

Ile-NH 2 ;

(SEQ ID NO: 364)

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Aib-NH 2 ;

(SEQ ID NO: 368)

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Pro-Ile-NH 2 ;

(SEQ ID NO: 376)

Occ-ala-Phe-arg-Leu-Hyp-Nml-Asp-Pro-Ile-NH 2 ;

(SEQ ID NO: 377)

Occ-ala-Phe-Apc-Leu-Hyp-Nml-Asp-Pro-Ile-NH 2 ;

(SEQ ID NO: 378)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Pro-Ile-NH 2 ;

(SEQ ID NO: 379)

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Aze-Ile-NH 2 ;

(SEQ ID NO: 380)

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Pip-Ile-NH 2 ;

(SEQ ID NO: 382)

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Eaz-Ile-NH 2 ;

(SEQ ID NO: 383)

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Cpp-Ile-NH 2 ;

(SEQ ID NO: 384)

Occ-ala-Phe-leu-Leu-Tap-Nml-Asp-Pro-Ile-NH 2 ;

(SEQ ID NO: 385)

Occ-ala-Phe-Apc-Leu-Hyp-Nml-Asp-Pro-Ile-NH 2 ;

(SEQ ID NO: 391)

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Apc-Ile-NH 2 ;

(SEQ ID NO: 394)

Occ-ala-Phe-dap(6238)-Leu-Tap-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 395)

Occ-ala-Phe-dap(3846)2-Leu-Tap-Nml-Asp-Arg-

Ile-NH 2 ;

(SEQ ID NO: 397)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Pro-558;

(SEQ ID NO: 399)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Pro-Ile-(NH-CH 3 );

(SEQ ID NO: 400)

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Chy-Ile-NH 2 ;

(SEQ ID NO: 401)

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-H3p-Ile-NH 2 ;

(SEQ ID NO: 402)

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Dhp-Ile-NH 2 ;

(SEQ ID NO: 403)

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Udp-Ile-NH 2 ;

(SEQ ID NO: 404)

Occ-ala-Phe-leu-Leu-Hyp-Nml-Asp-Bhk-Ile-NH 2 ;

(SEQ ID NO: 405)

Occ-Sni-Nif-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 407)

Occ-Sni-Pmy-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 410)

Occ-Sni-Eay-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 411)

Occ-Sni-Paf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 415)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Pro-2118;

(SEQ ID NO: 417)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Pro-1381;

(SEQ ID NO: 418)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Pro-1381;

(SEQ ID NO: 420)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Pro-1906;

(SEQ ID NO: 424)

Occ-Sni-Phe-Leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 430)

Occ-Sni-Phe-Gly-Leu-Tap-Nml-Asp-Pro-Ile-NH 2 ;

(SEQ ID NO: 434)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Nmr-Ile-NH 2 ;

(SEQ ID NO: 441)

Occ-Sni-Phe-dap(Me2)-Nml-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 444)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Val-Pro-Che;

(SEQ ID NO: 446)

Occ-Sni-Phe-leu-Leu-Hyp-Ile-Asp-Pro-Che;

(SEQ ID NO: 450)

Occ-Sni-Phe-Gly-Leu-Hyp-Nml-Asp-Pro-Che;

(SEQ ID NO: 451)

Occ-Sni-Phe-Apc-Leu-Hyp-Nml-Asp-Pro-Che;

(SEQ ID NO: 458)

4734-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 459)

4703-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 461)

Hex-(3421)-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-

Ile-NH 2 ;

(SEQ ID NO: 472)

Occ-Sni-Phe-leu-Leu-Hyp-Chg-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 475)

Occ-(aFL)-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 476)

Occ-(afL)-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 478)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Eal-Che;

(SEQ ID NO: 479)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-(ES-283-049);

(SEQ ID NO: 480)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Glu-Pro-Che;

(SEQ ID NO: 483)

779-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 485)

1281-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 487)

6013-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 494)

Occ-Sni-Phe-leu-Leu-Tap-Nml-(BB726)-Pro-Che;

(SEQ ID NO: 501)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Apc(Gly)-Che;

(SEQ ID NO: 503)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-(BB785)-Che;

(SEQ ID NO: 513)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Ble-Arg-Che;

(SEQ ID NO: 520)

Occ-Sni-Phe-orn(Me2)-Leu-Hyp-Nml-Val-Arg-Che;

(SEQ ID NO: 522)

Occ-Sni-Phe-lys(Me2)-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 527)

Occ-Sni-Phe-dab(Me2)-Leu-Hyp-Nml-Val-Arg-Ile-NH 2 ;

(SEQ ID NO: 528)

Occ-Nhpr-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 529)

Occ-Nbhp-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 530)

Occ-ser-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 531)

Occ-hse-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 532)

Gluc-Aoa-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-

Ile-NH 2 ;

(SEQ ID NO: 534)

(1913)-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-

Ile-NH 2 ;

(SEQ ID NO: 536)

(1888)-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-

Ile-NH 2 ;

(SEQ ID NO: 539)

1888-hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 540)

H-Adx-hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 542)

Oct-Sni-Phe-leu-Leu-Tap-Nml-Val-Pro-Che;

(SEQ ID NO: 543)

Occ-Sni-Phe-orn(Me2)-Leu-Hyp-Nml-Val-Pro-Che;

(SEQ ID NO: 544)

Occ-Sni-Phe-orn(Me2)-Leu-Tap-Nml-Val-Pro-Che;

(SEQ ID NO: 546)

Oct-Sni-Phe-leu-Leu-Hyp-Nml-Val-Arg-Che;

(SEQ ID NO: 547)

Oct-Sni-Phe-leu-Leu-Tap-Nml-Val-Arg-Che;

(SEQ ID NO: 549)

Oct-Sni-Phe-orn(Me2)-Leu-Hyp-Nml-Val-Arg-Che;

(SEQ ID NO: 552)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Cpg-Arg-Ile-NH 2 ;

(SEQ ID NO: 554)

(AR-314-169)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 558)

(AR-314-172)-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 560)

Occ-Sni-Phe-hse-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 561)

Occ-Sni-Phe-abu(pip)-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 562)

(AR-385-042)-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 563)

Occ-Sni-Phe-Fbz-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 564)

Occ-Sni-Phe-Fhy-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 566)

Occ-Sni-Phe-his-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 567)

Occ-Sni-Phe-metO2-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 568)

Occ-Sni-Phe-(AR-385-017)-Leu-Hyp-Nml-Asp-Arg-

Ile-NH 2 ;

(SEQ ID NO: 569)

Occ-Sni-Phe-opa-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 570)

Occ-Sni-Phe-mpa-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 571)

Occ-Sni-Phe-ppa-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 573)

Occ-Sni-Phe-Eao-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 574)

Occ-Sni-Phe-Aic-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 575)

Occ-Sni-Phe-orn(Me2)-Leu-Hyp-Nml-Ser-Arg-Che;

(SEQ ID NO: 577)

H-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 578)

H-hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 579)

H-Lys-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 580)

H-Lys-hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 582)

(2857-Ac)-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-

Ile-NH 2 ;

(SEQ ID NO: 583)

(1625-Ac)-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 584)

Occ-Sni-Phe-orn(Me2)-Leu-Hyp-Nml-Dim-Arg-Ile-NH 2 ;

(SEQ ID NO: 587)

Occ-Sni-Phe-Dha-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 ;

(SEQ ID NO: 590)

Occ-Sni-Phe-orn(Me2)-Leu-Hyp-Nml-Pth-Arg-Che;

(SEQ ID NO: 591)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Pth-Arg-Che;

(SEQ ID NO: 592)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Ser-Arg-Ile-NH 2 ;

(SEQ ID NO: 594)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Cya-Arg-Ile-NH 2 ;

(SEQ ID NO: 595)

Occ-Sni-Phe-orn(Me2)-Leu-Hyp-Nml-Cya-Arg-Ile-NH 2 ;

(SEQ ID NO: 596)

Occ-Sni-Phe-orn(Me2)-Leu-Hyp-Nml-Thr-Arg-Ile-NH 2 ;

(SEQ ID NO: 597)

Occ-Sni-Phe-leu-Leu-Hyp(Asp(-))-Nml-Asp-Arg-

Ile-NH 2 ;

(SEQ ID NO: 599)

Occ-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-OH;

(SEQ ID NO: 600)

Occ-Sni-Phe-orn(Me2)-Leu-Hyp-Nml-Asp-Arg-Ile-OH;

(SEQ ID NO: 602)

Occ-Sni-Phe-leu-Leu-Tap(Asp(-))-Nml-Asp-Arg-

Ile-NH 2 .

2. The compound of claim 1 , wherein the compound is:

(SEQ ID NO: 22)

Hex-Ala-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-

Ala-NH 2 .

3. The compound of claim 1 , wherein the compound is:

(SEQ ID NO: 24)

Hex-Gly-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-

Ala-NH 2 .

4. The compound of claim 1 , wherein the compound is:

(SEQ ID NO: 25)

Hex-Gly-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-

Gly-NH 2 .

5. The compound of claim 1 , wherein the compound is:

(SEQ ID NO: 52)

Occ-Nip-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-NH 2 .

6. The compound of claim 1 , wherein the compound is:

(SEQ ID NO: 53)

Occ-ala-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-NH 2 .

7. The compound of claim 1 , wherein the compound is:

(SEQ ID NO: 62)

Occ-Sni-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-NH 2 .

8. The compound of claim 1 , wherein the compound is:

(SEQ ID NO: 68)

Occ-ala-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-2797.

9. The compound of claim 1 , wherein the compound is:

(SEQ ID NO: 86)

Occ-ala-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-1860.

10. The compound of claim 1 , wherein the compound is:

(SEQ ID NO: 90)

Occ-ala-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Che.

11. The compound of claim 1 , wherein the compound is:

(SEQ ID NO: 92)

Occ-ala-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-1934.

12. The compound of claim 1 , wherein the compound is:

(SEQ ID NO: 93)

Occ-ala-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-1906.

13. The compound of claim 1 , wherein the compound is:

(SEQ ID NO: 96)

Occ-ala-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-5119.

14. The compound of claim 1 , wherein the compound is:

(SEQ ID NO: 103)

Occ-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-1860.

15. The compound of claim 1 , wherein the compound is:

(SEQ ID NO: 107)

Occ-ala-Phe-Gly-Leu-Pro-Nml-Asp-Arg-Ile-NH 2 .

16. The compound of claim 1 , wherein the compound is:

(SEQ ID NO: 109)

Occ-ala-Phe-Gly-Leu-Hyp-Leu-Asp-Arg-Ile-NH 2 .

17. The compound of claim 1 , wherein the compound is:

(SEQ ID NO: 125)

Occ-aze-Phe-Gly-Leu-Pro-Leu-Asp-Arg-Ile-NH 2 .

18. The compound of claim 1 , wherein the compound is:

(SEQ ID NO: 126)

Occ-ala-Nmf-Gly-Leu-Pro-Nml-Asp-Arg-Ile-NH 2 .

19. The compound of claim 1 , wherein the compound is:

(SEQ ID NO: 128)

Occ-Sni-Phe-Gly-Leu-Pro-Nml-Asp-Arg-Ile-NH 2 .

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: OSTERKAMP, FRANK; KNAUTE, TOBIAS; RICHTER, UWE; HAWLISCH, HEIKO; REIMER, ULF; SIMON, BERNADETT; HELLBERG, MARK R.; HUMMEL, GERD; REINEKE, ULRICH; SPECKER, EDGAR; WOISCHNIK, MARKUS

To: ALCON RESEARCH, LTD.

Reel/Frame 034844/0777 →

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 12888556 · Sep 23, 2010

Provisional Application 61245960 · Sep 25, 2009

Related Publication 20130345394A1 · Dec 26, 2013