Molecular modelling and conformational analysis of novel glycoprotein (Gp) IIb/IIIa antagonists. Molecular orbital calculation and the condensed heterocyclic derivatives.
A naphthalene compound was chosen as lead compound to develop a new series of fibrinogen receptor antagonists. Eight new compounds with different condensed heterocyclic parts were prepared and their in vitro activities were evaluated. 5-Amidinobenzofuran compound 2, 6-amidinobenzothiophene 7, and 5-amidinofuro[2,3-b]pyridine 8 were more active than lead compound 1. Molecular orbital calculation studies suggested the presence of a preferred spatial orientation between the amidine and the carboxylic acid.
Ono
S
S
Exploratory Reseach II, Drug Discovery Laboratories, Welfide Corporation, 2-25-1 Shodai-Ohtani, Hirakata, 573-1153, Osaka, Japan. onos@welfide.co.jp
Inoue
Y
Y
Yoshida
T
T
Kosaka
K
K
Maeda
K
K
Imada
T
T
Fukaya
C
C
Nakamura
N
N
D000085:Acetates / Q000737:chemistry* / Q000494:pharmacology*; D000578:Amidines / Q000737:chemistry* / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011487:Protein Conformation; D013329:Structure-Activity Relationship
C412594:2-(((5-amidinobenzofuran-2-yl)formamido)phenyloxy)acetic acid; C412593:2-(((5-amidinofuro(2,3-b)pyridin-2-yl)formamido)phenyloxy)acetic acid; C412592:2-(((6-amidinobenzothiophene-2-yl)formamido)phenyloxy)acetic acid; D000085:Acetates; D000578:Amidines; D006571:Heterocyclic Compounds; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex