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(12) United States Patent (10) Patent No.: US 8,524,654 B2 Blalock Et Al

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(12) United States Patent (10) Patent No.: US 8,524,654 B2 Blalock Et Al USOO8524654B2 (12) United States Patent (10) Patent No.: US 8,524,654 B2 Blalock et al. (45) Date of Patent: Sep. 3, 2013 (54) PROLYL ENDOPEPTIDASE INHIBITORS 5,506,256 A 4/1996 Kobayashi et al. FOR REDUCING OR PREVENTING SEF, A 3: byshi et al. ea. NEUTROPHILIC INFLAMMATION 5,756,763 A 5/1998 Takeuchi et al. 5,965,556 A 10/1999 Takeuchi et al. (75) Inventors: J. Edwin Blalock, Birmingham, AL 6,875,851 B1 4, 2005 kills a (US); Uros V. Djekic, Rockville, MD 6,878,751 B1* 4/2005 Donnelly et al. ............. 514,733 (US); Patricia L. Jackson, Moody, AL 2004.5. R 1238. ShingSorge etstal al. (US);S. BrettR SENoerager, ESN Birmingham, ALAL 2007/00213602005/0014699 A1 1/20071/2005 NyceAnsorge et al. et al. (US); Philip J. O'Reilly, Hoover, AL (US) FOREIGN PATENT DOCUMENTS EP O286928 4f1988 (73) Assignee: The UAB Research Foundation, EP O384341 8, 1990 Birmingham, AL (US) WO WO9012005 10, 1990 OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this Thorax, Aug. 1, 2007.vil 62, No. 8,706-713, published online on Feb. patent is extended or adjusted under 35 20, 2007.* U.S.C. 154(b) by 552 days. Marti et al., “Prolyl endopeptidase-mediated destruction of T cell epitopes in whole gluten: chemical and immunological characteriza (21) Appl. No.: 12/601,216 tion.” J. Pharmacol. Exp. Ther. 312:19-26 (2005). Matter et al., “Quantitative structure—activity relationship of human (22) PCT Filed: May 21, 2008 neutrophil collagenase (MMP-8) inhibitors using comparative molecular field analysis and X-ray structure analysis. J. Med. Chem. 42: 1908-20 (2007). (86). PCT No.: PCT/US2O08/064404 Morain et al., “Pharmacodynamic and pharmacokinetic profile of S S371 (c)(1) 17092, a new orally active prolyl endopeptidase inhibitor, in elderly (2), (4) Date:. Jan. 7, 2010 healthy(2000). volunteers. A phase I study.” Br. J. Clin. Pharmacol. 50:350-9 Morain et al., “S 10792: A prolyl endopeptidase inhibitor as a poten (87) PCT Pub. No.: WO2008/144748 tial therapeutic drug for memory impairment, Preclinical and clinical studies.” CNS Drug Reviews 8:31-52 (2002). PCT Pub. Date: Nov. 27, 2008 Morain et al., “Psychotropic profile of S 17092, a prolyl O O endopeptidase inhibitor, using quantitative EEG in young healthy (65) Prior Publication Data volunteers.” Neuropsychobiology 55:176-83 (2007). US 2010/O16798O A1 Jul. 1, 2010 Nishikata et al., “Synthesis and structure of prolinal-containing • us peptides, and their use as specific inhibitors of prolyl endopeptidases.” Chem. Pharm. Bull. 34:2931-6 (1986). O O Nozaki et al., “Prolyl endopeptidase purified from granulomatous Related U.S. Application Data inflammation in mice.” J. Cell. Biochem. 49:296-303 (1992). (60) Provisional application No. 60/939,290, filed on May O'Donnell et al., “Inflammatory cells in the airways in COPD.” 21, 2007. Thorax 61:448-54 (2006). s Olivo et al., “Representative aminopeptidases and prolyl endopeptidase from murine macrophages: comparative activity lev (51) Int. Cl. els in resident and elicited cells.' Biochem Pharmacol. 69: 1441-50 A6 IK38/00 (2006.01) (2005). A6 IK3I/58 (2006.01) O'Reilly et al., “Interfering with extracellular matrix degradation to (52) U.S. Cl. pyOWSK agains. OOTWC Opin. 2VeS RAIR OCOOO 1aWage USPC - - - - - - - - - - - grrrrr. 514/1.1; 514/176 fluids: cathepsin B SS and E. ISE J. E. (58) Field of Classification Search Med. 97:467-76 (1981). None Pfister et al., “Preliminary characterization of a polymorphonuclear See application file for complete search history. leukocyte stimulant isolated from alkali-treated collagen.” Invest. Ophthamol. Vis. Sci. 29:955-62 (1988). (56) References Cited (Continued) U.S. PATENT DOCUMENTS Primary Examiner — Marcela M Cordero Garcia 4,810,721 A 3, 1989 Saitoh et al. Assistant Examiner — Kaipeen Yang 4,912,127 A 3/1990 Henning et al. (74) Attorney, Agent, or Firm — Kilpatrick, Townsend & 4,977, 180 A 12/1990 Toda et al. Stockton LLP 4,983,624 A 1/1991 Toda et al. 4,999,349 A 3/1991 Toda et al. (57) ABSTRACT 5,028,604 A 7, 1991 Torizuka et al. Provided herein are methods for reducing or preventing neu 5,073,549 A 12/1991 Toda et al. trophilic inflammation in a subject comprising selecting a : A 23: Ea al subject with Or at risk. for neutrophilic inflammation and 5. 1 iss 11 A 6, 1992 Uchida et al. administering to the Subject an agent that inhibits the expres 5, 198458 A 3/1993 Higuchi et al. sion or activity of prolyl endopeptidase. Provided herein are 5,254,550 A 10, 1993 Toda et al. also methods for treatment or prevention of diseases associ 5,262.431. A 1 1/1993 Toda et al. ated with neutrophilic inflammation. 5,407,950 A 4/1995 Okubo et al. 5.449,750 A 9, 1995 Kimura et al. 28 Claims, 5 Drawing Sheets US 8,524,654 B2 Page 2 (56) References Cited Yoshimoto et al., “Postproline cleaving enzyme: identification as serine protease using active site specific inhibitors. Biochem. OTHER PUBLICATIONS 16:2942 (1977). 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Barelli et al., “S 17092-1, a highly potent, specific and cell permeant Riley et al., “Neutrophil response following intratracheal instillation inhibitor of human proline endopeptidase.” Biochem. Biophys. Res. of collagen peptides into rat lungs.” Exp. Lung. Res. 14:549-63 Commun. 257:657-61 (1999). (1988). Bellemere et al., “Effect of S 17092, a novel prolyl endopeptidase Rosenblum et al., “Prolyl peptidases: a serine protease subfamily inhibitor, on Substance P and O-melanocyte-stimulating hormone with high potential for drug discovery.” Curr. Opin. Chem. Biol. breakdown in the rat brain.” J. Neurochem. 84:919-29 (2003). 7:496-504 (2003). Berton et al., “Involvement of fibronectin type II repeats in the effi Rowe et al., “Mechanisms of disease: cystic fibrosis.” N. Engl. J. cient inhibition of gelatinases A and B by long-chain unsaturated Med. 352: 1992-2001 (2005). fatty acids.” J. Biol. Chem. 276:20458-65 (2001). Saito et al., “Synthesis and inhibitory activity of acyl-peptidyl-pyr Cheng et al., “How can the mood stabilizer VPA limit both mania and rolidine derivatives toward post-proline cleaving enzyme: a study of depression?.” Mol. Cell. Neurosci. 29:155-61 (2005). subsite specificity.” J. Enz. Inhib. Med. Chem. 5:51-75 (1991). Doring, “The role of neutrophil elastase on chronic inflammation.” Schneider et al., “Effects of prolyl endopepdase inhibitor S 17092 on Am. J. Resp. Crit. Care Med. 150:S1 14-7 (1994). cognitive deficits in chronic low dose MPTP-treated monkeys.” Doring and Worlitzsch, “Inflammation in cystic fibrosis and its man Neuropsychobiology 26:176-82 (2002). agement.” Paediatr. Respir. Rev. 1:101-6 (2000). Sedo et al., “Dipeptidyl peptidase IV, prolyl endopeptidase and Emingil et al., “The effect of adjunctive low-dose doxycycline cathepsin B activities in primary human lung tumors and lung paren therapy on clinical parameters and gingival crevicular fluid matrix chyma.” J. Canc. Res. Clin. Oncol. 1 17:249-53 (1991). metalloproteinase-8 levels in chronic periodontitis.” J. Periodontol. Senior et al., "Chemotactic activity of elastin-derived peptides,” J. 75: 106-15 (2004). Clin. Invest. 66:859-62 (1980). Foronjy et al., “Progressive adult-onset emphysema in transgenic Shan et al., “Structural and mechanistic analysis of two prolyl mice expressing human MMP-1 in the lung.” Am. J. Physiol. Lung endopeptidases: role of interdomain dynamics in catalysis and speci Cell Mol. Physiol. 284:L727-37 (2003). ficity.” Proc. Natl. Acad. Sci. USA 102:3599-604 (2005). Friedman et al., “Prolyl endopeptidase: inhibition in vivo by Shoji et al., “Depression of prolylendopeptidase activity in the N-benzyloxycarbonyl-prolyl-prolinal.” J. Neurochem, 42:237-41 delayed hyperSensitive guinea pig skin lesion induced by bovine (1984). gamma-globulin.” Biochem. Int. 18:1 183-92 (1989). Fryberget al., “Possible role of MMP-9 in collagen fragmentation for Smith et al., “Specificity of inhibition of matrix metalloproteinase bronchiolitis obliterans syndrome.” American Thoracic Society activity by doxycycline: relationship to structure of the enzyme.” Annual Meeting; San Fran.
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