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Agonists of Guanylate Cyclase Useful for the Treatment of Gastrointestinal Disorders, Inflammation, Cancer and Other Disorders

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Agonists of Guanylate Cyclase Useful for the Treatment of Gastrointestinal Disorders, Inflammation, Cancer and Other Disorders (19) TZZ ¥__T (11) EP 2 998 314 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 23.03.2016 Bulletin 2016/12 C07K 7/08 (2006.01) A61K 38/10 (2006.01) A61K 47/48 (2006.01) A61P 1/00 (2006.01) (21) Application number: 15190713.6 (22) Date of filing: 04.06.2008 (84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • SHAILUBHAI, Kunwar HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT Audubon, PA 19402 (US) RO SE SI SK TR • JACOB, Gary S. New York, NY 10028 (US) (30) Priority: 04.06.2007 US 933194 P (74) Representative: Cooley (UK) LLP (62) Document number(s) of the earlier application(s) in Dashwood accordance with Art. 76 EPC: 69 Old Broad Street 12162903.4 / 2 527 360 London EC2M 1QS (GB) 08770135.5 / 2 170 930 Remarks: (71) Applicant: Synergy Pharmaceuticals Inc. This application was filed on 21-10-2015 as a New York, NY 10170 (US) divisional application to the application mentioned under INID code 62. (54) AGONISTS OF GUANYLATE CYCLASE USEFUL FOR THE TREATMENT OF GASTROINTESTINAL DISORDERS, INFLAMMATION, CANCER AND OTHER DISORDERS (57) The invention provides novel guanylate cycla- esterase. The gastrointestinal disorder may be classified se-C agonist peptides and their use in the treatment of as either irritable bowel syndrome, constipation, or ex- human diseases including gastrointestinal disorders, in- cessive acidity etc. The gastrointestinal disease may be flammation or cancer (e.g., a gastrointestinal cancer). classified as either inflammatory bowel disease or other The peptides can be administered either alone or in com- GI condition, including Crohn’s disease and ulcerative bination with an inhibitor of cGMP-dependent phosphodi- colitis, and cancer. EP 2 998 314 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 998 314 A1 Description RELATED APPLICATIONS 5 [0001] This application claims the benefit of priority to U.S. Provisional Application No. 60/933,194 filed on June 4, 2007, the contents of which is incorporated by reference in its entirety. FIELD OF THE INVENTION 10 [0002] The present invention relates to the therapeutic use of guanylate cyclase C (GC-C) agonists as a means for enhancing the intracellular production of cGMP. The agonists may be used either alone or in combination with inhibitors of cGMP-specific phosphodiesterase to prevent or treat inflammation, cancer and other disorders, particularly of the gastrointestinal tract and the lung. 15 BACKGROUND OF THE INVENTION [0003] Uroguanylin, guanylin and bacterial ST peptides are structurally related peptides that bind to a guanylate cyclase receptor and stimulate intracellular production of cyclic guanosine monophosphate (cGMP) (1-6). This results in the activation of the cystic fibrosis transmembrane conductance regulator (CFTR), an apical membrane channel for efflux 20 of chloride from enterocytes lining the intestinal tract (1-6). Activation of CFTR and the subsequent enhancement of transepithelial secretion of chloride lead to stimulation of sodium and water secretion into the intestinal lumen. Therefore, by serving as paracrine regulators of CFTR activity, cGMP receptor agonists regulate fluid and electrolyte transport in the GI tract (1-6; US patent 5,489,670). Thus, the cGMP-mediated activation of CFTR and the downstream signaling plays an important role in normal functioning of gut physiology. Therefore, any abnormality in this process could potentially 25 lead to gastrointestinal disorders such as irritable bowel syndrome, inflammatory bowel disease, excessive acidity and cancer (25, 26). [0004] The process of epithelial renewal involves the proliferation, migration, differentiation, senescence, and eventual loss of GI cells in the lumen (7, 8). The GI mucosa can be divided into three distinct zones based on the proliferation index of epithelial cells. One of these zones, the proliferative zone, consists of undifferentiated stem cells responsible 30 for providing a constant source of new cells. The stem cells migrate upward toward the lumen to which they are extruded. As they migrate, the cells lose their capacity to divide and become differentiated for carrying out specialized functions of the GI mucosa (9). Renewal of GI mucosa is very rapid with complete turnover occurring within a 24-48 hour period (9). During this process mutated and unwanted cells are replenished with new cells. Hence, homeostasis of the GI mucosa is regulated by continual maintenance of the balance between proliferation and apoptotic rates (8). 35 [0005] The rates of cell proliferation and apoptosis in the gut epithelium can be increased or decreased in a wide variety of different circumstances, e.g., in response to physiological stimuli such as aging, inflammatory signals, hor- mones, peptides, growth factors, chemicals and dietary habits. In addition, an enhanced proliferation rate is frequently associated with a reduction in turnover time and an expansion of the proliferative zone (10). The proliferation index has been observed to be much higher in pathological cases of ulcerative colitis and other GI disorders (11). Thus, intestinal 40 hyperplasia is the major promoter of gastrointestinal inflammation and carcinogenesis. [0006] In addition to a role for uroguanylin and guanylin as modulators of intestinal fluid and ion secretion, these peptides may also be involved in the continual renewal of GI mucosa by maintaining the balance between proliferation and apoptosis in cells lining GI mucosa. Therefore, any disruption in this renewal process, due to reduced production of uroguanylin and/or guanylin can lead to GI inflammation and cancer (25, 26). This is consistent with previously 45 published data in WO 01/25266, which suggest a peptide with the active domain of uroguanylin may function as an inhibitor of polyp development in the colon and may constitute a treatment of colon cancer. However, recent data also suggest that uroguanylin also binds to a currently unknown receptor, which is distinct from GC-C receptor (3,4). Knockout mice lacking this guanylate cyclase receptor show resistance to ST peptides in the intestine, but effects of uroguanylin and ST peptides are not disturbed in the kidney in vivo (3). These results were further supported by the fact that membrane 50 depolarization induced by guanylin was blocked by genistein, a tyrosine kinase inhibitor, whereas hyperpolarization induced by uroguanylin was not effected (12, 13). Thus, it is not clear if the anti-colon cancer and anti-inflammatory activities of uroguanylin and its analogs are mediated through binding to one or both of these receptors. [0007] Inflammatory bowel disease is a general name given to a group of disorders that cause intestines to become inflamed, characterized by red and swollen tissue. Gastrointestinal (GI) inflammation can be a chronic condition and 55 often leads to GI cancer (14). Examples of such inflammatory bowel diseases (IBD) include Crohn’s disease and ulcerative colitis (UC). It is estimated that as many as 1,000,000 Americans are afflicted with IBD, with male and female patients appearing to be equally affected. Most cases are diagnosed before age 30, but the disease can occur in the sixth, seventh, and later decades of life. 2 EP 2 998 314 A1 [0008] Crohn’s disease is a serious inflammatory disease that predominantly effects ileum and colon, but can also occur in other sections of the GI tract, whereas UC is exclusively an inflammatory disease of the colon, the large intestine (15). Unlike Crohn’s disease, in which all layers of the intestine are involved, and in which there can be normal healthy bowel in between patches of diseased bowel, UC affects only the innermost lining (mucosa) of the colon in a continuous 5 manner (16). Depending on which portion of the GI tract is involved, Crohn’s disease may be referred to as ileitis, regional enteritis, colitis, etc. Crohn’s disease and UC differ from spastic colon or irritable bowel syndrome, which are motility disorders of the GI tract. [0009] While the precise cause of IBD is not known, it is believed that the disruption of the process of continual renewal of GI mucosa may be involved in disease (17,18). The renewal process of the GI lining is an efficient and dynamic 10 process involving the continual proliferation and replenishment of unwanted damaged cells. Proliferation rates of cells lining the GI mucosa are very high, second only to the hematopoietic system. Thus, the balance between proliferation and apoptosis is important to the maintenance of the homeostasis of the GI mucosa (19,20). [0010] GI homeostasis depends on both proliferation and programmed cellular death (apoptosis) of epithelial cells lining the gut mucosa. Hence, cells are continually lost from the villus into the lumen of the gut and are replenished at 15 a substantially equal rate by the proliferation of cells in the crypts, followed by their upward movement to the villus. It has become increasingly apparent that the control of cell death is an equally, if not more, important regulator of cell number and proliferation index (19,20). Reduced rates of apoptosis are often associated with abnormal growth, inflam- mation, and neoplastic transformation. Thus, both decreased proliferation and/or increased cell death may reduce cell number, whereas increased proliferation and/or reduced cell death may increase the proliferation index of intestinal 20 tissue (20), which may lead to GI inflammatory diseases and cancer. [0011] Uroguanylin and guanylin peptides also appear to promote apoptosis by controlling
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