Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor
| Data(s) |
10/06/2010
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| Resumo |
During the course of our research efforts to develop a potent and selective gamma-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-beta precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of gamma-secretase (A beta 40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced A beta 40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs. |
| Identificador |
http://dx.doi.org/10.1021/ml1000239 http://www.scopus.com/inward/record.url?scp=77954122667&partnerID=8YFLogxK |
| Idioma(s) |
eng |
| Direitos |
info:eu-repo/semantics/restrictedAccess |
| Fonte |
Gillman , K W , Starrett , J E , Parker , M F , Xie , K , Bronson , J J , Marcin , L R , McElhone , K E , Bergstrom , C P , Mate , R A , Williams , R , Meredith , J E , Burton , C R , Barten , D M , Toyn , J H , Roberts , S B , Lentz , K A , Houston , J G , Zaczek , R , Albright , C F , Decicco , C P , Macor , J E & Olson , R E 2010 , ' Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor ' ACS MEDICINAL CHEMISTRY LETTERS , vol 1 , no. 3 , pp. 120-124 . DOI: 10.1021/ml1000239 |
| Palavras-Chave | #/dk/atira/pure/subjectarea/asjc/1600/1605 #Organic Chemistry #/dk/atira/pure/subjectarea/asjc/3000/3002 #Drug Discovery #/dk/atira/pure/subjectarea/asjc/1300/1303 #Biochemistry |
| Tipo |
article |
