US 20090036364A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0036364 A1 Levy et al. (43) Pub. Date: Feb. 5, 2009 (54) GIPANALOG AND HYBRID POLYPEPTIDES (86). PCT No.: PCT/US2O06/OOSO2O WITH SELECTABLE PROPERTIES S371 (c)(1), (75) Inventors: Odile Esther Levy, San Diego, CA (2), (4) Date: May 21, 2008 (US); Alain D. Baron, San Diego, Related U.S. Application Data CA (US); Lawrence J. D’Souza, San Diego, CA (US); Mary (60) Provisional application No. 60/652,662, filed on Feb. Erickson, San Diego, CA (US); 11, 2005, provisional application No. 60/651,647, Soumitra S. Ghosh, San Diego, CA filed on Feb. 11, 2005, provisional application No. (US); Michael R. Hanley, San 60/653,433, filed on Feb. 15, 2005, provisional appli Diego, CA (US); Samuel Janssen, cation No. 60/707,244, filed on Aug. 11, 2005, provi San Diego, CA (US); Carolyn M. sional application No. 60/707,369, filed on Aug. 11, Jodka, San Diego, CA (US); Diana 2005, provisional application No. 60/709,320, filed on Y. Lewis, San Diego, CA (US); Aug. 17, 2005, provisional application No. 60/709, Christine M. Mack, San Diego, 316, filed on Aug. 17, 2005. CA (US); David G. Parkes, San Diego, CA (US); Richard A. Publication Classification Pittner, San Diego, CA (US); (51) Int. Cl. Christopher J. Soares, San Diego, A638/22 (2006.01) CA (US); Ved Srivastava, San C07K I4/47 (2006.01) Diego, CA (US); Andrew A. A6IP3/10 (2006.01) Young, San Diego, CA (US) (52) U.S. Cl. ........................................... 514/12:530/324 Correspondence Address: (57) ABSTRACT Intellectual Property Department The present invention relates generally to novel GIP analogs Amylin Pharmaceuticals, Inc. and GIP hybrid polypeptides with selectable properties, use 9360 Towne Centre Drive ful as agents for the treatment and prevention of metabolic San Diego, CA 92121 (US) diseases and disorders, for example those which can be alle viated by control plasma glucose levels, insulin levels, and/or (73) Assignee: Amylin Pharmaceuticals, Inc., San insulin secretion, positive inotropic effects, reduction of cata Diego, CA (US) bolic effects, slowing of gastric emptying. Such conditions and disorders include, but are not limited to, hypertension, (21) Appl. No.: 11/816,095 dyslipidemia, cardiovascular disease, eating disorders, criti cal care, insulin-resistance, obesity, and diabetes mellitus of (22) PCT Filed: Feb. 10, 2006 any kind, including type 1, type 2, and gestational diabetes. Patent Application Publication Feb. 5, 2009 Sheet 1 of 78 US 2009/0036364 A1 Fig. 1 Patent Application Publication Feb. 5, 2009 Sheet 2 of 78 US 2009/0036364 A1 Patent Application Publication US 2009/0036364 A1 poola:1190asoon19u?=Bue?5ç?edesaynullºpºol?=saen|$g Patent Application Publication Feb. 5, 2009 Sheet 4 of 78 US 2009/0036364 A1 Fig. 4 Glucose Lowering Assay: Change in blood glucose - as his - Cmd., 800 mingkg -- Cmd; 80 nmolkg s O Š- -- Cmd H 8 mTorkg XN- -- Cmad K 8 minorkg --° N \ N - N— 8 t s - T -- - - - O 8. Patent Application Publication Feb. 5, 2009 Sheet 5 of 78 US 2009/0036364 A1 ?OuenbeS ‘ONpunoduoOCIIOES Patent Application Publication Feb. 5, 2009 Sheet 6 of 78 US 2009/0036364 A1 ?ouanbaS ‘ONpunoduuOOCIIOES Patent Application Publication Feb. 5, 2009 Sheet 7 of 78 US 2009/0036364 A1 ?ouembæS ‘ONpunoduoOCIIOES Patent Application Publication Feb. 5, 2009 Sheet 8 of 78 US 2009/0036364 A1 ?Ouenb3S ‘ONpunoduOOCIIOES 999c)||5)|0908/ 0Z8||CH|5)|0906/ .ON Patent Application Publication Feb. 5, 2009 Sheet 9 of 78 US 2009/0036364 A1 Fig. 6 OH --OH HN OH H:NY OH HN H HN X OH O O O Agy = ?lylglycine D-hs3-hydroxy-3- (R)-2-amino- Hse L-Hofnosefire Aib- AfTinoisobutyric acic methyllitanoic acic H HHOH HNNH, *C OH '-...-0 H H H- H HN Jso HN H O Ahk (S)-2-amino-3- rhethbutanoichydroxy- acid FTEthylaetanoicairo-3-hydroxy- acid Thr(GalNAca) hR = L-homoarginine C HN 'h C NH" H 3. H NH HN H H so H HN OH HM H C O Lys(Fir) = L-N. A. - - e firinylysine Cit = - Citruline Orni L-Ornithine h = -Honolysine O S-r-,OH H 9-MIKOKONANOICAC (ANC) 4-AMINOBUTYRIC ACID (ABU) Patent Application Publication Feb. 5, 2009 Sheet 10 of 78 US 2009/0036364 A1 5 apa = FinOC-5 an ino peritanoic acid O 12 c = FTC-12 aftino docleCaric acic FMOC-S-N-Ml OH Tinipeg(8) = FinOC-3,6-dioxyodanoic acid FMOC --o-o-o: Tinieg (13) = Frnoc-1-amino-4,7,10-trioxa-13-triclecanarnine succininic acid re-o-o-o-o-'. Patent Application Publication Feb. 5, 2009 Sheet 11 of 78 US 2009/0036364 A1 c r see Lucy sustar Patent Application Publication Feb. 5, 2009 Sheet 12 of 78 US 2009/0036364 A1 Fig. 9 Change in blood glucose - Wehicle --CmpdH 80mmol/kg O --Cmpd G 80mmol/kg 18O O minutes Patent Application Publication Feb. 5, 2009 Sheet 13 of 78 US 2009/0036364 A1 s r s essed Loi afuer Patent Application Publication Feb. 5, 2009 Sheet 14 of 78 US 2009/0036364 A1 Fig.11 120.O --a2GIP(1-30)-Ex(31-39) --G|P(1-42) 100.0 -A-GP(1-30) 80.0 - 60.0 40.0 - 20.0 Patent Application Publication Feb. 5, 2009 Sheet 15 of 78 US 2009/0036364 A1 C OC O c olio |0 |H |0 O . :ON oII /09 80€. |||& Patent Application Publication Feb. 5, 2009 Sheet 16 of 78 US 2009/0036364 A1 cy ed cy n cy cy r cy cy N cd v CY on ed on n CY Y cN w N Y ch on s N Cd v- c. Y- C wr N wr R w- w v- c. R. 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