Tricyclic pharmacophore-based molecules as novel integrin alpha(v)beta3 antagonists. Part 1: design and synthesis of a lead compound exhibiting alpha(v)beta3/alpha(IIb)beta3 dual antagonistic activity.
In order to generate novel compounds with integrin alpha(v)beta3-antagonistic activity together with antiplatelet activity, tricyclic pharmacophore-based molecules were designed and synthesized. Although piperazine-containing compounds initially prepared were selective alpha(IIb)beta3 antagonists, replacement of piperazine with piperidine furnished a potent alpha(v)beta3/alpha(IIb)beta3 dual antagonist. Structure-activity relationship (SAR) studies provided clues for further development of tricyclic pharmacophore-based integrin antagonists.
Kubota
Dai
D
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.
Ishikawa
Minoru
M
Yamamoto
Mikio
M
Murakami
Shoichi
S
Hachisu
Mitsugu
M
Katano
Kiyoaki
K
Ajito
Keiichi
K
D001011:Aorta / Q000166:cytology; D002448:Cell Adhesion / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019096:Vitronectin / Q000737:chemistry
D039302:Integrin alphaVbeta3; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019096:Vitronectin