Discovery of nonpeptidic small-molecule AP-1 inhibitors: lead hopping based on a three-dimensional pharmacophore model.
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.
Tsuchida
Keiichi
K
Discovery Laboratories, Toyama Chemical Co., Ltd., 4-1 Shimookui 2-chome, Toyama 930-8508, Japan. keiichi_tuchida@toyama-chemical.co.jp
Chaki
Hisaaki
H
Takakura
Tadakazu
T
Kotsubo
Hironori
H
Tanaka
Tadashi
T
Aikawa
Yukihiko
Y
Shiozawa
Shunichi
S
Hirono
Shuichi
S
D000818:Animals; D001577:Benzophenones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004247:DNA / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*
D001577:Benzophenones; D004791:Enzyme Inhibitors; D013141:Spiro Compounds; D018808:Transcription Factor AP-1; C047723:benzophenone; D004247:DNA