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(12) United States Patent (10) Patent No.: US 8,097.590 B2 Pinel Et Al

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(12) United States Patent (10) Patent No.: US 8,097.590 B2 Pinel Et Al USO08097590B2 (12) United States Patent (10) Patent No.: US 8,097.590 B2 Pinel et al. (45) Date of Patent: Jan. 17, 2012 (54) o-MSH-ANTAGONIST DIPEPTIDE FOREIGN PATENT DOCUMENTS CONUGATES EP O 389 95.0 A1 10, 1990 EP O 669938 B1 9, 1995 (75) Inventors: Anne-Marie Pinel, Toulouse (FR): E. : 29: R 1928 Pascal Verdie, Saint Mathieu de Treviers EP 1174 437 A1 1, 2002 (FR); Pascaline Dubs, Montpellier (FR): FR 1327363 5, 1962 Jean Martinez, Caux (FR); Gilles FR 2805744 A1 9, 2001 Subra, Juvignac (FR) FR 2810 323 A1 12/2001 s GB 1 OOO 897 8, 1965 (73) Assignees: Centre National de la Recherche W. W. 2.95. A. 3E Scientifique (CNRS), Paris (FR): WO WO 98.25584 A1 6, 1998 Institut Europeen de Biologie W. W. 9.3. A. 358: Cellulaire, Ramonville St. Agne (FR): WO WO O2/O85925 A2 10, 2002 Universite de Montpellier I, WO WO 03/064.458 A2 8, 2003 Montpellier (FR); Universite de WO WOO3,O95474 A2 11/2003 Montpellier II, Montpellier (FR) WO WO 2004/099237 A1 11, 2004 WO WO 2004/110341 A2 12/2004 (*) Notice: Subject to any disclaimer, the term of this WO WO 2005,116068 A1 12/2005 patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 1143 days. Stverteczky et al., Acta Chimica Academiae Scientiarum (21) Appl. No.: 11/596,286 Hungaricae, 1975, vol. 87, No. 3, pp. 269-283.* Baumann et al., “Specificity of O-chyrinotrypsin dipeptide Sub (22) PCT Filed: May 10, 2005 strates.” FEBS Letters, Jun. 1970, 8(5), 257-260. Beekman et al., “Synthetic peptide vaccines: palmitoylation of (86). PCT No.: PCT/FR2OOS/OO1164. peptide antigens by a thioester bond increases immunogenicityk, J. Peptide Res., 1997, 50: 357-364. S371 (c)(1), Chhajlani, Vijay, "Characterization of a Putative C-MSHAntagonist (2), (4) Date: May 23, 2007 153N-6 at Melanocortin Receptor Subtypes by Radioligand Bind ing.” Peptides, 1996, 17(2), 349-351. (87) PCT Pub. No.: WO2005/115174 Cone et al., “The Melanocortin Receptors: Agonists, Antagonists, and the Hormonal Control of Pigmentation.” Recent Progress in PCT Pub. Date: Dec. 8, 2005 Hormone Research, 1996, 51:287-317. Feliu et al., “Spiroimidazolidinone Library Derivatives on SynPhase (65) Prior Publication Data Lanterns. J. Comb. Chem., 2003, 4:356-361. US 2007/O231284 A1 Oct. 4, 2007 (Continued) (30) Foreign Application Priority Data Primary Examiner — Christopher R. Tate May 11, 2004 (FR) ...................................... O4 O5069 Assistant Examiner — Roy Teller Oct. 22, 2004 (FR) ...................................... O4 11279 (74) Attorney, Agent, or Firm — Foley & Lardner LLP (51) Int. Cl. C07C 229/00 (2006.01) (57) ABSTRACT (52) U.S. Cl. ............................. 514/19:514/558; 424/62 The invention relates to a dipeptide conjugate having general (58) Field of Classification Search ........................ None formula I, AA2-AA1-NH, wherein A represent the radical See application file for complete search history. corresponding to a monocarboxylic acid with general for mula II, HOOC R, in which: R represents a linear or (56) References Cited branched aliphatic radical at C-C which is optionally Sub stituted by a hydroxyl group and which can comprise one or U.S. PATENT DOCUMENTS more unsaturations, preferably between 1 and 6 unsatura 5,674,839 A 10/1997 Hruby et al. tions, and/or which can comprise a phenyl group or lipoic 5,714,576 A 2/1998 Hruby et al. acid or the reduced form thereof, dihydrolipoic acid or N-li 5,719, 126 A 2, 1998 Nordlund et al. poyllysine; and AA1 and AA2 represent identical or different 5,786.332 A 7, 1998 Girten et al. 5.830,994. A 1 1/1998 D'Hinterland et al. amino acids which are selected from the group containing 6,054,556 A 4/2000 Hruby et al. Ala, Asn. Cys, Gln, Gly, Ile, Leu, Met, Phe, Pro, Ser. Thr, Trp, 6,228,840 B1 5, 2001 Wei et al. Tyr, Val, Asp, Glu, Arg, His, Lys, Orn, Dap, Dab, the corre 6,245,342 B1 6/2001 Golz-Berner et al. sponding homo-amino acids and the corresponding beta 3.35 R 33 t et al. amino acids in the form of enantiomers or diastereoisomers 65.79848 B1 6/2003 Hearing, Jr. and mixtures thereof, including racemic mixtures. 2003/0194445 A1 10, 2003 Kuhner et al. 2004/0010010 A1 1/2004 Ebetino et al. 2005. O187164 A1 8, 2005 Pinel 9 Claims, No Drawings US 8,097.590 B2 Page 2 OTHER PUBLICATIONS Vogler et al., “Basic peptides containing fatty acids with an anti bacterial action.” 1964, 47:526-544, ZP002062066, and its English Haskell-Luevano et al., “Truncation Studies of O-Melanotropin translation. 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Hadley et al., “Biological Activities of Melanotropic Peptide Fatty Holder et al., “Structure-Activity Relationships of the Melanocortin Acid Conjugates.” Pigment Cell Research, 1991, 4:180-185. Tetrapeptide Ac-His-D-Phe-Arg-Trp-NH2 at the Mouse Haskell-Luevano et al., “Characterization of Melanocortin NDP Melanocortic Receptors. 1. Modifications at the His Position.” J. MSHAgonist Peptide Fragments at the Mouse Central and Periph Med. Chem., 2002, 45:2801-2810. eral Melanocortin Receptors.” J. Med. Chem., 2001, 44, 2247-2252. Hruby et al., “Design, Synthesis, and Conformation of Superpotent Haskell-Luevano et al., “Discovery of Prototype Peptidomimetic and Prolonged Acting Melanotropins.” Ann. N.Y. Acad. Sci., 1993, Agonists at the Human Melanocortin Receptors MC1R and MC4R.” 680:51-63. J. Med. Chem., 1997, 40:2133-2139. Jacubovich et al., "Tumour-associated Antigens in Culture Medium Hiltz et al., “Alpha-MSH Peptides Inhibit Acute Inflammation and of Malignant Melanoma Cell Strains.” Cancer Immunol. contact Sensitivity.” Peptides, 1990, 11:979-982. Immunother, 1979, 7:59-64. Koikov et al., “Analogs of sub-nanomolar hMC1R agonist LK-184 Jayawickreme et al., “Discovery and Structure-Function Analysis of Ph(CH2)3CO-His-D-Phe-Arg-Trp-NH2). An additional binding O-Melanocyte-stimulating Hormone Antagonists. J. Biol. Chem. site within the human melanocortin receptor 12'. Bioorganic & Nov. 25, 1994, 269(47), 2.9846-298.54. Medicinal Chemistry Letters, 2004, 14:3997-4000. Lerner et al., “Effect of O- and 3-melanocyte stimulating hormones Koikov et al., "Sub-Nanomolar hMC1RAgonists by End-Capping of on the skin colour of man.” Nature, Jan. 21, 1961, 189: 176-179. Lopez-Fandino et al., “Protease-Catalyzed Synthesis of the Melanocortin Tetrapeptide His-D-Phe-Arg-Trp-NH2.” Oligopeptides in Heterogenous Substrate Mixtures.” Biotechnology Bioorganic & Medicinal Chemistry Letters, 2003, 13:2647-2650. and Bioengineering, 1994, 43:1024-1030. Lipton, James M.. “Modulation of Host Defense by the Neuropeptide Lu et al., “Agouti protein is an antagonist of the melanocyte-stimu C-MSH,”Yale Journal of Biology and Medicine, 1990, 63:173-182. lating-hormone receptor.” Nature, Oct. 27, 1994, 371:799-802. Tatro et al., “Specific Receptors for C-Melanocyte-Stimulating Hor Mountjoy et al., “The Cloning of a Family of Genes That Encode the moneAreWidely Distributed in Tissues of Rodents.” Endocrinology, Melanocortin Receptors.” Science, Aug. 28, 1992, 257:1248-1251. 1987, 121(5): 1900-1907. Nijenhuis et al., “Discovery and in vivo evaluation of new Todorovic et al., “N-Terminal Fatty Acylated His-DPhe-Arg-Trp melanocortin-4 receptor-selective peptides.” Peptides, 2003, 24:271 NH2 Tetrapeptides: Influence of Fatty Acid Chain Length of Potency 280. and Selectivity at the Mouse Melanocortin Receptors and Human Ollmann et al., “Antagonism of Central Melanocortin Receptors in Melanocytes.” J. Med. Chem., 2005, 48:3328-3336. Vitro and in Vivo by Agouti-Related Protein.” Science, Oct. 3, 1997. Yasumura et al., “Establishment of FourFunctional, Clonal Strains of 2.78:135-138. Animal Cells in Culture. Science, 1996, 154: 1186-1189. Quillan et al., “Combinatorial diffusion assay used to identify topi International Search Report issued in application No. PCT/FR2005/ cally active melanocyte-stimulating hormone receptor antagonists.” 001166 on Oct. 10, 2005. Proc. Natl. Acad. Sci. USA, Mar. 1995,92:2894-2898. 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