Safety, Pharmacokinetics and Pharmacodynamics Study of Treatment With CHF 5074 in Healthy Young Male Subjects

Summary

The purpose of this study is to evaluate the safety and tolerability of single oral doses of CHF 5074 in young healthy male volunteers.

Timeline

Start

2009-10

Primary completion

2010-05

Completion

2010-05

Publications

• Background Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006 Mar 16;440(7082):352-7. doi: 10.1038/nature04533.
• Background Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med. 2008 Aug;14(8):837-42. doi: 10.1038/nm1782. Epub 2008 Jun 22.
• Background Olson RE, Albright CF. Recent progress in the medicinal chemistry of gamma-secretase inhibitors. Curr Top Med Chem. 2008;8(1):17-33. doi: 10.2174/156802608783334088.
• Background Lleo A. Activity of gamma-secretase on substrates other than APP. Curr Top Med Chem. 2008;8(1):9-16. doi: 10.2174/156802608783334060.
• Background Lewis HD, Perez Revuelta BI, Nadin A, Neduvelil JG, Harrison T, Pollack SJ, Shearman MS. Catalytic site-directed gamma-secretase complex inhibitors do not discriminate pharmacologically between Notch S3 and beta-APP cleavages. Biochemistry. 2003 Jun 24;42(24):7580-6. doi: 10.1021/bi034310g.
• Background Maillard I, Adler SH, Pear WS. Notch and the immune system. Immunity. 2003 Dec;19(6):781-91. doi: 10.1016/s1074-7613(03)00325-x.
• Background Stanger BZ, Datar R, Murtaugh LC, Melton DA. Direct regulation of intestinal fate by Notch. Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12443-8. doi: 10.1073/pnas.0505690102. Epub 2005 Aug 17.
• Background Searfoss GH, Jordan WH, Calligaro DO, Galbreath EJ, Schirtzinger LM, Berridge BR, Gao H, Higgins MA, May PC, Ryan TP. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J Biol Chem. 2003 Nov 14;278(46):46107-16. doi: 10.1074/jbc.M307757200. Epub 2003 Aug 29.
• Background Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ, Zhang L, Higgins GA, Parker EM. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem. 2004 Mar 26;279(13):12876-82. doi: 10.1074/jbc.M311652200. Epub 2004 Jan 6.
• Background Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, Findlay KA, Smith TE, Murphy MP, Bulter T, Kang DE, Marquez-Sterling N, Golde TE, Koo EH. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature. 2001 Nov 8;414(6860):212-6. doi: 10.1038/35102591.
• Background Kukar T, Golde TE. Possible mechanisms of action of NSAIDs and related compounds that modulate gamma-secretase cleavage. Curr Top Med Chem. 2008;8(1):47-53. doi: 10.2174/156802608783334042.
• Background Peretto I, La Porta E. Gamma-secretase modulation and its promise for Alzheimer's disease: a medicinal chemistry perspective. Curr Top Med Chem. 2008;8(1):38-46. doi: 10.2174/156802608783334097.
• Background Peretto I, Radaelli S, Parini C, Zandi M, Raveglia LF, Dondio G, Fontanella L, Misiano P, Bigogno C, Rizzi A, Riccardi B, Biscaioli M, Marchetti S, Puccini P, Catinella S, Rondelli I, Cenacchi V, Bolzoni PT, Caruso P, Villetti G, Facchinetti F, Del Giudice E, Moretto N, Imbimbo BP. Synthesis and biological activity of flurbiprofen analogues as selective inhibitors of beta-amyloid(1)(-)(42) secretion. J Med Chem. 2005 Sep 8;48(18):5705-20. doi: 10.1021/jm0502541.
• Background Imbimbo BP, Del Giudice E, Colavito D, D'Arrigo A, Dalle Carbonare M, Villetti G, Facchinetti F, Volta R, Pietrini V, Baroc MF, Serneels L, De Strooper B, Leon A. 1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a novel gamma-secretase modulator, reduces brain beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease without causing peripheral toxicity. J Pharmacol Exp Ther. 2007 Dec;323(3):822-30. doi: 10.1124/jpet.107.129007. Epub 2007 Sep 25.
• Background Imbimbo BP, Del Giudice E, Cenacchi V, Volta R, Villetti G, Facchinetti F, Riccardi B, Puccini P, Moretto N, Grassi F, Ottonello S, Leon A. In vitro and in vivo profiling of CHF5022 and CHF5074 Two beta-amyloid1-42 lowering agents. Pharmacol Res. 2007 Apr;55(4):318-28. doi: 10.1016/j.phrs.2006.12.010. Epub 2007 Jan 16.
• Background Imbimbo BP, Hutter-Paier B, Villetti G, Facchinetti F, Cenacchi V, Volta R, Lanzillotta A, Pizzi M, Windisch M. CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease. Br J Pharmacol. 2009 Mar;156(6):982-93. doi: 10.1111/j.1476-5381.2008.00097.x.
• Background Sisti R, Nyska A. CHF 5074: 4-week oral toxicity study in rats followed by a 4-week recovery period. RTC Study No. 71470. February 9, 2009.
• Background Grassetti A, Nyska A. CHF 5074. 4 week oral toxicity study in dogs followed by a 4 week recovery period. RTC Study No. 71470. February 4, 2009.
• Background Cinelli S, Oberto G. CHF 5074. Unscheduled DNA Synthesis (UDS) in primary rat hepatocytes after in vivo treatment (autoradiographic methods). RTC Study No. 70270. December 4, 2008.
• Background Ciliutti P, Oberto G. CHF 5074. Micronucleous test in rats. RTC Study No. 70260. November 28, 2008.

Drugs

Indications