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(US); Mark Currie, Sterling, MA (US); 225, 33 SE: G US008779090B2 (12) United States Patent (10) Patent No.: US 8,779,090 B2 Zimmer et al. (45) Date of Patent: Jul. 15, 2014 (54) METHODS AND COMPOSITIONS FOR THE (56) References Cited TREATMENT OF HEART FAILURE AND U.S. PATENT DOCUMENTS OTHERDISORDERS M 5,518,888 A * 5/1996 Waldman ..................... 435/723 (75) Inventors: Daniel Zimmer, Somerville, MA (US); 7,304,036 B2 12/2007 Currie et al. Angelika Fretzen, Somerville, MA 7,371,727 B2 5/2008 Currie et al. (US); Mark Currie, Sterling, MA (US); 225, 33 SE: G. Todd Milne, Brookline, MA (US) 2004/0266989 Al 12/2004 Curtie et al. 2006/0281682 A1 12/2006 Currie et al. (73) Assignee: Ironwood Pharmaceuticals, Inc., 2009,019 1611 A1 7, 2009 Currie et al. Cambridge, MA (US) 2009,0253634 A1 10, 2009 Currie et al. (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 WO WO99/09416 A2 2?1999 U.S.C. 154(b) by 1147 days. WO WO2004O71436 A2 2/2004 WO WO 2004O71436 A2 * 8, 2004 (21) Appl. No.: 12/528,737 WO WO2005087797 A1 9, 2005 OTHER PUBLICATIONS (22) PCT Filed: Feb. 26, 2008 The Mayo Clinic Colon Cancer Symptoms http://www. (86). PCT No.: PCT/US2008/054972 mayoclinic.com/health/colon-cancer/DS00035/ DSECTION=symptoms, last visited Jun. 24, 2013.* S371 (c)(1), McMillan, Assessing and Managing Opiate-Induced Constipation in (2), (4) Date: Sep. 28, 2010 Adults with Cancer, Cancer Control, vol. 11, Supp. 1, No. 3, May/ Jun. 2004. (87) PCT Pub. No.: WO2008/106429 Lussier Adjuvant Analgesics in Cancer Pain, The Oncologist, vol. 9, pp. 571-591, 2004.* PCT Pub. Date: Sep. 4, 2008 Wolfe, H.R. et al., “A comparative molecular field analysis (COMFA) of the structural determinants of heat-stable enterotoxins (65) Prior Publication Data mediating activation of guanylyl cyclase C. J. of Med. Chem. Vol. 45(8): 1731-1734, Apr. 11, 2002. US 2011 FOO21419 A1 Jan. 27, 2011 Kubota, H., et al., “A Long-acting Heat-stable Enterotoxin Analog of US 2012/0040892 A9 Feb. 16, 2012 Enterotoxigenic Escherichia coli with a Single D-Amino Acid”, Biochem. and BioPhys. Research Communications vol. 161(1):229 235, May 30, 1989. Related U.S. Application Data * cited by examiner (60) Provisional application No. 60/891,626, filed on Feb. 26, 2007. Primary Examiner — James H Alstrum Acevedo Assistant Examiner — Jeanette Lieb (51) Int. Cl. (74) Attorney, Agent, or Firm — Honigman Miller Schwartz A6 IK38/04 (2006.01) & Cohn; Kelly T. Murphy; Jonathan P. O'Brien serie Cool) (57) ABSTRACT USPC .......................... 530/327, 514/16.4: 514/215 Peptides that act as GC-C receptor agonists and contain at (58) Field of Classification Search least one D-cys and are useful for the treatment of diuresis and None heart disease as well as other disorders are described. See application file for complete search history. 1 Claim, 64 Drawing Sheets U.S. Patent Jul. 15, 2014 Sheet 14 of 64 US 8,779,090 B2 Gly Cys Cys Glu Tyr D-Cys Cys Asn Pro Ala Cys Thr Gly D-Cys - Gly Cys Cys Glu Tyr D-Cys Cys Asn Pro Ala Cys Thr Gly (D-Cys Lys Gly Cys Cys Glu Tyr D-Cys Cys Asn Pro Ata Cys Thr Gly D-Cys Tyr Gly Cys Cys Glu Tyr D-Cys Cys Thr Pro Ata Cys Thr Gly Cys - Gly Cys Cys Giu Tyr D-Cys Cys Thr Pro Ala Cys Thr Gly Cys Lys Gly Cys Cys Glu Tyr D-Cys Cys Thr Pro Ala Cys Thr Gly Cys Tyr Gly Cys Cys Glu Tyr D-Cys Cys Thr Pro Aa Cys Thr Gly D-Cys - Gly Cys Cys Glu Tyr D-Cys Cys Thr Pro Aa Cys Thr Gly D-Cys Lys Gly Cys Cys Glu Tyr D-Cys Cys Thr Pro Ala Cys Thr Gly D-Cys yr O Gly Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys thr Gly Cys - Gly Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Lys Gly Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr u- Gly Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys thr Gly D-Cys - -- Gly Cys. Cys. Gu Phe Cys Cys Asn Pro Ala Cys Thr Gly D-Cys Lys OD Gly Cys Cys Glu Phe Cys Cys Asn Pro Ala Cys. Thr Gly D-Cys Tyr aA Gly Cys Cys Glu Phe Cys Cys Thr Pro Ala Cys Thr Gly Cys - Gly Cys Cys Glu Phe Cys Cys. Thir Pro Aa Cys Thr Gly Cys Lys Gly Cys Cys Glu Phe Cys Cys Thur Pro Ala Cys Thr Gly Cys Tyr reur Gly Cys Cys Glu Phe Cys Cys Thur Pro Aa Cys Thr Gly DeCys - area Gly Cys Cys Glu Phe Cys Cys Thur Pro Ala Cys Thr Gly D-Cys Lys Kaw Gly Cys Cys Giu Phe Cys Cys Thr Pro Aa Cys Thr Gly D-Cys Tyr Gly Cys Cys Glu Phe D-Cys Cys Asn Pro Ala Cys Thr Gly Cys -- Ap Gly Cys Cys Glu Phe D-Cys Cys Asn Pro Aa Cys Thr Gly Cys lys r Gly Cys Cys Glu Phe D-Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr MD Gly Cys Cys. Gu Phe D-Cys Cys Asn Pro Ala Cys Thr Gly O-Cys - r Gly Cys Cys. Gu Phe D-Cys Cys Asn Pro Ala are Gly Cys Cys. Gu Phe D-Cys Cys Asn Pro Ala OO Gly Cys. Cys. Gu Pha D-Cys Cys Thr Pro Ala Gly Cys Cys Giu Phe D-Cys Cys Thr Pro Ala Thr Gly Cys Cya Glu Phe D-Cys Cys Thr Pro Aa Cys. Thr Gly Cys Cys Glu Phe D-Cys Cys Thr Pro Ala r Gly Cys. Cys Glu Phe D-Cys Cys Thr Pro As r Gly Cys Cys Glu Phe D-Cys Cys Thr Pro Aa T DO Gly Cys Cys Glu Trp Cys Cys Asn Pro Ala Tr ana Gly Cys Cys Glu Trp Cys Cys Asn. Pro Ala Cys. Thr Gly Cys Lys ar Gly Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr o Gly Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr -- Gly Cys Cys Glu Trip Cys. Cys Asn. Pro Ala Cys. Thr Gly Cys Cys Giu Tp Cys Cys Asr Pro Ala Cys Thr up Gly Cys Cys Glu Trp Cys Cys Thr Pro Ala Cys. Thr per Gly Cys Cys Glu Tp Cys Cys Thr Pro Al Cys Thr Gly CyS Lys Gly Cys Cys. Gu Trp Cys Cys Thr Pro Ala Cys. Thr Gly Cys Tyr aga Gly Cys Cys GEu Trp Cys Cys Thr Pro Ala Cys Thr Gly Cys Cys. Gu Trp Cys Cys Thr Pro Ala Cys Thr Gly D-CyS Lys Gly Cys Cys. Gu Trp Cys Cys Thr Pro Ala Cys Thr Gly D-Cys Tyr Gly Cys Cys Glu Trp D-Cys Cys Asn Pro Ala Cys. Thr Gly Cys - Gly Cys Cys Giu Trp C-Cys Cys Asr Pro Ala Cys. Thir Gly CyS Lys area Gly Cys Cys Glu Tip D-Cys Cys As Pro Ala Cys Thr Gly Cys Tyr p Gly Cys Cys Gu Trp D-Cys Cys Asn Pro Ala Cys Thr Gly D-Cys as Gly Cys Cys Giu Trp O-Cys Cys Asn Pro Ala Cys. Thr Gly C-Cys Lys a Gly Cys Cys Giu Tip D-Cys Cys Asn Pro Ala Cys Thr Gly d-Cys Tyr wns Gly Cys Cys Glu Tip D-Cys Cys Thr Pro Aa Cys Thr Gly Cys ess Gly Cys Cys Glu Trp D-Cys. Cys tr Pro Ala Cys Thr Gly Cys Lys area Gly Cys Cys Giu Trp D-Cys. Cys Thr Pro Aa Cys Thr Gly Cys Tyr Gly Cys Cys Glu Trp O-Cys Cys Thr Pro Ala Cys Thr Gly (D-Cys - r Gly Cys Cys Glu Trp D-Cys. Cys Thr Pro Aa Cys Thr Gly O-Cys Lys --- Gly Cys Cys Glu Trp D-Cys Cys Thr Pro Ala Cys Thr Gly D-Cys Tyr e Gly D-Cys Cys Glu Val Cys Cys Asn Pro Ala Cys Thr Gly Cys - re- Gly D-Cys Cys Giu Wall Cys Cys Asn Pro As Cys Thr Gly Cys lys Gly D-Cys Cys Gu Val Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr FIG. 3A-12 U.S. Patent Jul. 15, 2014 Sheet 17 of 64 US 8,779,090 B2 -- Gly D-CyS Cys Giu Trp Cys Cys Asn Pro Ala Cys Thr Gly D-Cys -- --- Gly D-Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr Gly D-Cys Lys Gly D-Cys Cys Glu Trp Cys Cys Asn Pro Ala Cys Thr Gly (D-Cys Tyr --- Gly O-Cys Cys Glu Trp Cys Cys Thr Pro Ala Cys Thr Gly Cys - --- Gly O-Cys Cys Glu Trp Cys Cys Thr Pro Ala Cys Thr Gly Cys Lys am Gly D-Cys Cys Glu Trp Cys Cys Thr Pro Aa Cys Thr Gly Cys Tyr on- Gly D-Cys Cys Glu Trp Cys Cys Thr Pro Ala Cys Thr Gly D-Cys - - Gly D-Cys. Cys Glu Trp Cys Cys Thr Pro Ala Cys Thr Gly D-Cys Lys arra Gly D-Cys Cys Glu Trp Cys Cys Thr Pro Aa Cys Thr Gly D-Cys Tyr - Gly D-Cys Cys Glu Trp D-Cys Cys Asn Pro Ala Cys Thr Gly Cys - Gly D-Cys Cys Glu Trp D-Cys Cys Asn Pro Ala Cys Thr Gly Cys Lys Gly D-Cys Cys Glu Trp D-Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Gly D-Cys Cys Glu Trip D-Cys Cys Asn Pro Ala Cys thr Gly D-Cys re Gly D-Cys Cys Glu Trp D-Cys Cys Asn Pro Ala Cys Thr Gly (D-Cys Lys --ro Gly D-Cys Cys Glu Trp D-Cys Cys Asn Pro Ala Cys Thr Gly D-Cys Tyr area Gly D-Cys Cys Glu Tip D-Cys Cys Thr Pro Ala Cys Thr Gly Cys - on- Gly D-Cys Cys Glu Trp D-Cys Cys Thr Pro Ala Cys Thr Gly Cys Lys --- Gly D-Cys Cys Glu Tip D-Cys Cys Thr Pro Aa Cys Thr Gly Cys Tyr -- Gly (D-Cys Cys Glu Tip D-Cys Cys Thr Pro Ala Cys Thr Gly (D-Cys - -- Gly D-Cys Cys Glu Trp D-Cys Cys Thr Pro Aa Cys Thr Gly D-Cys Lys Gly D-Cys Cys Glu Trp D-Cys Cys Thr Pro Ala Cys Thr Gly D-Cys Tyr --- Lys Cys Cys Glu Val Cys Cys Asn Pro Ala Cys Thr Gly Cys - -- Lys.
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