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J Med Chem. 2006 Jan 12;49(1):80-91.

Discovery of nonpeptidic small-molecule AP-1 inhibitors: lead hopping based on a three-dimensional pharmacophore model.

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1
Discovery Laboratories, Toyama Chemical Co., Ltd., 4-1 Shimookui 2-chome, Toyama 930-8508, Japan. keiichi_tuchida@toyama-chemical.co.jp

Abstract

We designed and synthesized small-molecule activator protein-1 (AP-1) inhibitors based on a three-dimensional (3D) pharmacophore model that we had previously derived from a cyclic decapeptide exhibiting AP-1 inhibitory activity. New AP-1 inhibitors with a 1-thia-4-azaspiro[4.5]decane or a benzophenone scaffold, which inhibit the DNA-binding and transactivation activities of AP-1, were discovered using a "lead hopping" procedure. An additional investigation of the benzophenone analogues confirmed the reliability of the pharmacophore model, its utility to discover AP-1 inhibitors, and the potency of the benzophenone derivatives as a lead series.

PMID:
16392794
DOI:
10.1021/jm050550d
[Indexed for MEDLINE]
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