Autor: |
Taveras AG; Department of Chemistry and Tumor Biology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. arthur.taveras@spcorp.com, Aki C, Chao J, Doll RJ, Lalwani T, Girijavallabhan V, Strickland CL, Windsor WT, Weber P, Hollinger F, Snow M, Patton R, Kirschmeier P, James L, Liu M, Nomeir A |
Jazyk: |
angličtina |
Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2002 Aug 29; Vol. 45 (18), pp. 3854-64. |
DOI: |
10.1021/jm010463v |
Abstrakt: |
The 10-bromobenzocycloheptapyridyl farnesyl transferase inhibitor (FTI) Sch-66336 (1) is currently under clinical evaluation for the treatment of human cancers. During structure-activity relationship development leading to 1, 10-bromobenzocycloheptapyridyl FTIs were found to be more potent than analogous compounds lacking the 10-Br substituent. This potency enhancement was believed to be due, in part, to an increase in conformational rigidity as the 10-bromo substituent could restrict the conformation of the appended C(11) piperidyl substituent in an axial orientation. A novel and potent class of FTIs, represented by indolocycloheptapyridine Sch-207758 [(+)-10a], have been designed based on this principle. Although structural and thermodynamic results suggest that entropy plays a crucial role in the increased potency observed with (+)-10a through conformational constraints and solvation effects, the results also indicate that the indolocycloheptapyridine moiety in (+)-10a provides increased hydrophobic interactions with the protein through the addition of the indole group. This report details the X-ray structure and the thermodynamic and pharmacokinetic profiles of (+)-10a, as well as the synthesis of indolocycloheptapyridine FTIs and their potencies in biochemical and biological assays. |
Databáze: |
MEDLINE |
Externí odkaz: |
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