Tricyclic pharmacophore-based molecules as novel integrin alpha(v)beta3 antagonists. Part III: synthesis of potent antagonists with alpha(v)beta3/alpha(IIb)beta3 dual activity and improved water solubility.
In order to optimize our novel integrin alpha(v)beta3/alpha(IIb)beta3 dual antagonists, spatial screening at the N-terminus was performed. The alpha(v)beta3 antagonistic activity varied depending on the space that was occupied by the N-terminus, but high potency against alpha(IIb)beta3 was well maintained. The (3S)-aminopiperidine analogue had the strongest activity against alpha(v)beta3, and the S isomer at piperidine was more potent than the R isomer. Compounds selected on the basis of SAR analysis of a novel lead compound showed acceptable early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and sufficient water solubility for use as infusion drugs. Docking studies with the alpha(v)beta3 receptor were performed to confirm the SAR findings.
Ishikawa
Minoru
M
Pharmaceutical Research Department, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. minoru_ishikawa@meiji.co.jp
Hiraiwa
Yukiko
Y
Kubota
Dai
D
Tsushima
Masaki
M
Watanabe
Takashi
T
Murakami
Shoichi
S
Ouchi
Shokichi
S
Ajito
Keiichi
K
D000818:Animals; D001011:Aorta / Q000166:cytology; D002448:Cell Adhesion / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008958:Models, Molecular; 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*; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019096:Vitronectin / Q000737:chemistry; D014867:Water / Q000737:chemistry
C481395:4-aminopiperidine; D039302:Integrin alphaVbeta3; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019096:Vitronectin; D014867:Water