Dibasic benzo[B]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 4. SAR studies on the conformationally restricted C3-side chain of hydroxybenzo[B]thiophenes

K Takeuchi; T J Kohn; D J Sall; M L Denney; J R McCowan; G F Smith; D S Gifford-Moore

doi:10.1016/s0960-894x(99)00076-1

Dibasic benzo[B]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 4. SAR studies on the conformationally restricted C3-side chain of hydroxybenzo[B]thiophenes

Bioorg Med Chem Lett. 1999 Mar 8;9(5):759-64. doi: 10.1016/s0960-894x(99)00076-1.

Authors

K Takeuchi¹, T J Kohn, D J Sall, M L Denney, J R McCowan, G F Smith, D S Gifford-Moore

Affiliation

¹ Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.

PMID: 10201843
DOI: 10.1016/s0960-894x(99)00076-1

Abstract

A novel series of benzo[b]thiophene diamine thrombin inhibitors with a conformationally restricted C3-side chain 3 was investigated. The constrained C3-side chain by a cyclohexyl ring contributed to not only an additive but also a synergistic effect on the thrombin inhibitory activity. The SAR studies resulted in the discovery of a potent thrombin inhibitor 27 that was over 750-fold more potent than the initial lead compound 1.

MeSH terms

Structure-Activity Relationship
Thiophenes / chemistry*
Thiophenes / pharmacology
Thrombin / antagonists & inhibitors*

Substances

Thiophenes
benzothiophene
Thrombin