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Syntheses and initial evaluation of a series of indolo-fused heterocyclic inhibitors of the polymerase enzyme (NS5B) of the hepatitis C virus |
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| Authors: | Zheng Xiaofan Hudyma Thomas W Martin Scott W Bergstrom Carl Ding Min He Feng Romine Jeffrey Poss Michael A Kadow John F Chang Chong-Hwan Wan John Witmer Mark R Morin Paul Camac Daniel M Sheriff Steven Beno Brett R Rigat Karen L Wang Ying-Kai Fridell Robert Lemm Julie Qiu Dike Liu Mengping Voss Stacey Pelosi Lenore Roberts Susan B Gao Min Knipe Jay Gentles Robert G |
| Affiliation: | a Discovery Chemistry and Candidate Optimization, Bristol Myers Squibb, Research and Development, 5 Research Parkway, Wallingford CT 06492, United States b Virology Biology, Bristol Myers Squibb, Research and Development, 5 Research Parkway, Wallingford CT 06492, United States c Bristol Myers Squibb, Research and Development, US Route 206 and Province Line Road, Lawrenceville, NJ 08540, United States |
| Abstract: | Herein, we present initial SAR studies on a series of bridged 2-arylindole-based NS5B inhibitors. The introduction of bridging elements between the indole N1 and the ortho-position of the 2-aryl moiety resulted in conformationally constrained heterocycles that possess multiple additional vectors for further exploration. The binding mode and pharmacokinetic (PK) properties of select examples, including: 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[2,1-d][1,4]benzodiazepine-10-carboxylic acid (7) (IC50 = 0.07 μM, %F = 18), are reported. |
| Keywords: | NS5B HCV Indolo-fused heterocyclic inhibitors |
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