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ACDTATC VTHRLAGLLSR SGGVVKNNFV Privgskaf CONH2 - O-Helix Turn Turn Turn Disulfide Patent Application Publication Jan

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ACDTATC VTHRLAGLLSR SGGVVKNNFV Privgskaf CONH2 - O-Helix Turn Turn Turn Disulfide Patent Application Publication Jan US 2008.0020978A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0020978 A1 Gegg, JR. et al. (43) Pub. Date: Jan. 24, 2008 (54) CGRP PEPTIDE ANTAGONSTS AND Related U.S. Application Data CONUGATES (60) Provisional application No. 60/729,083, filed on Oct. (76) Inventors: Colin V. Gegg JR., Newbury Park, CA 21, 2005. (US); Eileen J. Johnson, Newbury Park, CA (US); Leslie P. Miranda, Publication Classification Thousand Oaks, CA (US); Kenneth W. Walker, Newbury Park, CA (US); (51) Int. Cl. Jerry Ryan Holder, Simi Valley, CA A6II 38/00 (2006.01) (US); Marie E. Wright, Westlake A6IP 43/00 (2006.01) Village, CA (US); Derin C. D'Amico, (52) U.S. Cl. ................................................................ S14/12 Newbury Park, CA (US) (57) ABSTRACT Correspondence Address: AMGEN INC. Disclosed is a composition of matter that involves a CGRP MAIL STOP 28-2-C peptide antagonist. A pharmaceutical composition is dis ONE AMGEN CENTER DRIVE closed that comprises the composition of matter and a THOUSAND OAKS, CA 91320-1799 (US) pharmaceutically acceptable carrier, which can be config ured for administration to a patient. Also disclosed is a (21) Appl. No.: 111584,177 method of producing the composition of matter. Methods of treating, preventing or mitigating migraine, are also dis (22) Filed: Oct. 19, 2006 closed. Structure of human OCGRP Shaded residues have been implicated in receptor binding. 1-7 8-18 19-27 28-37 receptor activation receptor binding hinge region receptor binding ACDTATC VTHRLAGLLSR SGGVVKNNFV privgSKAF CONH2 - O-helix turn turn turn disulfide Patent Application Publication Jan. 24, 2008 Sheet 1 of 11 US 2008/0020978A1 F.G. 1 Structure of human OCGRP Shaded residues have been implicated in receptor binding. 1-7 8-18 19-27 28-37 receptor activation receptor binding hinge region receptor binding ACDTATC VTHRLAGLLSR SGGVVKNNFV pnvgSKAF CONH2 O-helix turn turn turn disulfide FG. 2 M8 M2 SGGVVIRKNFVPTDVGPFAF – NH M7 AC - visit M6 M1 Patent Application Publication Jan. 24, 2008 Sheet 2 of 11 US 2008/0020978A1 O O (NY)H an-Ns.H ASp-LyS LyS-ASp 3r ? re Glu-Lys Lys-Glu O O Homo-Glu-Lys Lys-Homo-Glu O O OnN rolN M Cpa-LyS Y M LyS-Cpa Mr O O N-1). an-NS.H ASp-Orn Orn-Asp ''H "H Glu-Orn Orn-Glu O O r-N-).H an-NY).H Homo-Glu-Orn Orn-Homo-Glu O O ElN J.N Cpa-Orn Orn-Cpa Patent Application Publication Jan. 24, 2008 Sheet 3 of 11 US 2008/0020978 A1 FG. 4. 1 Control 25% 50%. 25% 50%. 25% 50%. 25% 50% MeOH MeOH EtOH EtOH IPA IPA. TFE TFE O 145678OOOOOO ID # 7 ID # 7 ID # 7 ID # 31 ID #31 Di 31 Control + 50% + 50% Control + 50% + 50% IPA TFE PA TFE Patent Application Publication Jan. 24, 2008 Sheet 4 of 11 US 2008/0020978A1 % COSolvent -G- PA -v- TFE -- HFIPA Patent Application Publication Jan. 24, 2008 Sheet 5 of 11 US 2008/0020978A1 F.G. 7 90 80 70 60 50 40 30 20 10 O 20 40 60 80 % COSolvent -G- PA -v- TFE -- HFPA Patent Application Publication Jan. 24, 2008 Sheet 6 of 11 US 2008/0020978A1 FG. 8 80 70 60 50 40 30 20 10 O 20 40 60 80 % COSOlwent -e- IPA -v- TFE -- HFPA Patent Application Publication Jan. 24, 2008 Sheet 8 of 11 US 2008/0020978A1 eoUepundV eNee Patent Application Publication Jan. 24, 2008 Sheet 9 of 11 US 2008/0020978A1 s M O C. Cd O O C C Co S 33 d N CO LO r cr) CN re eOUepUnqWeNee Patent Application Publication Jan. 24, 2008 Sheet 10 of 11 US 2008/0020978A1 eOuepunqy eNee US 2008/0020978 A1 Jan. 24, 2008 CGRP PEPTIDE ANTAGONSTS AND that recognize regulatory peptides such as secretin, glucagon CONUGATES and vasoactive intestinal polypeptide (VIP). The best char acterized splice variants of human CT receptor differ 0001) This application claims the benefit of U.S. Provi depending on the presence (formerly CTR or CTR1, now sional Application No. 60/729,083, filed Oct. 21, 2005, known as CTs) or absence (the major splice variant, which is hereby incorporated by reference. formerly CTR, or CTR, now known as CT) of 16 amino 0002 This application incorporates by reference all Sub acids in the first intracellular loop. (Gorn et al., Expression ject matter contained on the compact disc, which is identi of two human skeletal calcitonin receptor isoforms cloned fied by the name of the file, A-1061.5T25.txt created on from a giant cell tumor of bone: the first intracellular domain October , 2006, the size of which file is KB. modulates ligand binding and signal transduction, J. Clin. Invest., 95:2680-2691 (1995); Hay et al., Amylin receptors: 0003. Throughout this application various publications molecular composition and pharmacology, Biochem. Soc. are referenced within parentheses. The disclosures of these Trans., 32:865-867 (2004); Poyner et al., 2002). The exist publications in their entireties are hereby incorporated by ence of at least two CGRP receptor subtypes had been reference in this application in order to more fully describe proposed from differential antagonist affinities and agonist the state of the art to which this invention pertains. potencies in a variety of in vivo and in vitro bioassays. (Dennis et al., CGRP8-37. A calcitonin gene-related peptide BACKGROUND OF THE INVENTION antagonist revealing calcitonin gene-related peptide receptor heterogeneity in brain and periphery, J. Pharmacol. Exp. 0004) 1. Field of the Invention Ther. 254:123-128 (1990); Dennis et al., Structure-activity 0005 The present invention is related to the biochemical profile of calcitonin gene-related peptide in peripheral and arts, in particular to therapeutic peptide conjugates. brain tissues. Evidence for receptor multiplicity, J. Pharma col. Exp. Ther. 251:718-725 (1989); Dumont et al. A potent 0006 2. Discussion of the Related Art and selective CGRP2 agonist, Cys(Et)2.7hCGRP: com 0007. The calcitonin (CT) superfamily of peptides parison in prototypical CGRP and CGRP2 in vitro assays, includes at least five known members: CT, amylin (AMY), Can. J. Physiol. Pharmacol., 75:671-676 (1997)). adrenomedulin (ADM), and two calcitonin gene-related 0009. The CGRP receptor subtype was found to be peptides, CGRP1 (also known as ctCGRP) and CGRP2 (also sensitive to the antagonist fragment CGRP(8-37). (Chiba et known as BCGRP). Calcitonin is involved in the control of al., Calcitonin gene-related peptide receptor antagonist bone metabolism and is also active in the central nervous human CGRP-(8-37), Am. J. Physiol., 256:E331-E335 system (CNS). Amylin also has specific binding sites in the (1989); Dennis et al. (1990); Mimeault et al., Comparative CNS and is thought to regulate gastric emptying and have a affinities and antagonistic potencies of various human cal role in carbohydrate metabolism. ADM is a potent vasodi citonin gene-related peptide fragments on calcitonin gene lator. ADM has specific receptors on astrocytes and its related peptide receptors in brain and periphery, J. Pharma messenger RNA is upregulated in CNS tissues that are col. Exp. Ther. 258:1084-1090 (1991)). By contrast, the Subject to ischaemia. (Zimmermann, et al., Identification of CGRP, receptor was sensitive to linear human CGRP adrenoinedullin receptors in cultured rat astrocytes and in (hCGRP) analogs, in which the cysteine residues at posi neuroblastoinaglioma hybrid cells (NG108-15), Brain Res., tions 2 and 7 were derivatized (e.g., with acetoaminomethyl 724:238-245 (1996); Wang et al., Discovery of adrenoin Cys(ACM) or ethylamide Cys(Et)7)) but CGRP, edullin in rat ischaemic cortex and evidence for its role in receptor was insensitive to fragment CGRP(8-37). (Dennis exacerbating focal brain ischaemic damage, Proc. Natl. et al. (1989); Dennis et al. (1990); Dumont et al. (1997)). In Acad. Sci. USA, 92:11480-11484 (1995)). The biological 1998, the CGRP receptor was identified as a heterodimer activities of CGRP include the regulation of neuromuscular composed of a novel single transmembrane domain acces junctions, of antigen presentation within the immune sys sory protein, receptor activity-modifying protein 1 tem, of vascular tone and of sensory neurotransinission. (RAMP1), and calcitonin receptor-like receptor (CRLR or (Poyner, D. R., Calcitonin gene-related peptide: multiple “CL”). (McLatchie et al., RAMPs regulate the transport and actions, multiple receptors, Pharmacol. Ther., 56:23-51 ligand specificity of the calcitonin-receptor-like receptor, (1992); Muff et al., Calcitonin, calcitonin gene related peptide, adrenomedullin and amylin: homologous peptides, Nature, 393:333-339 (1998)). separate receptors and overlapping biological actions, Eur. J. 0010 CRLR has 55% overall amino acid sequence iden Endocrinol., 133: 17-20 (1995)). Three calcitonin receptor tity with CT receptor, although the transmembrane domains stimulating peptides (CRSPs) have also recently been iden are almost 80% identical. (McLatchie et al. (1998); Poyner tified in a number of mammalian species; the CRSPs may et al., International union of pharmacology. XXXII. The form a new subfamily in the CGRP family, however, the mammalian calcitonin gene-related peptides, adrenomedul endogenous molecular forms, receptors, and biological lin, amylin and calcitonin receptors, Pharmacol. Rev., activity of the CRSPs remain unidentified. (Katafuchi, Tand 54:233-246 (2002)). Minamino, N, Structure and biological properties of three 0011 Ligand specificity of CT receptor and CRLR calcitonin receptor-stimulating peptides, novel members of depend on the coexpression of members of a family of the calcitonin gene-related peptide family, Peptides, accessory proteins called the receptor activity modifying 25(11):2039-2045 (2004)). proteins (RAMPs). The RAMP family includes three that act 0008. The CT superfamily peptides act through seven as receptor modulators that determine the ligand specificity transmembrane-domain G-protein-coupled receptors of receptors for the CT family members.
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