Novel non-peptide fibrinogen receptor antagonists. 1. Synthesis and glycoprotein IIb-IIIa antagonistic activities of 1,3,4-trisubstituted 2-oxopiperazine derivatives incorporating side-chain functions of the RGDF peptide.
Based on the lead tetrapeptide RGDF, two possible non-peptide glycoprotein (GP) IIb-IIIa antagonists possessing an (S)-2-oxopiperazine-3-acetic acid moiety as a scaffold incorporating the indispensable Asp fragment were prepared, and (S)-4-[[trans-[4-(guanidinomethyl)-cyclohexyl]carbonyl]glycyl]-2- oxopiperazine-1,3-diacetic acid, 1a, was identified as a potential lead. A series of 3-substituted 2-oxopiperazine-1-acetic acids bearing the Arg-Gly equivalent at the 4-position were prepared and evaluated for their ability to prevent platelet aggregation and for their binding affinity for the GP IIb-IIIa receptor purified from human HEL cells. (S)-4-[(4-Amidinobenzoyl)glycyl]-3-[(methoxycarbonyl)methyl]- 2-oxopiperazine-1-acetic acid, 9 (TAK-029), inhibited in vitro human platelet aggregation with an IC50 value of 0.03 microM and GP IIb-IIIa-fibrinogen binding with an IC50 value of 0.49 nM. The [4-(2-aminoethyl)benzoyl]glycyl derivative 26 showed activity comparable to that of 9 (IC50 = 0.093 microM, guinea pig platelet aggregation assay). Compound 9 dose-dependently inhibited ex vivo platelet aggregation in guinea pigs (0.03 and 0.1 mg/kg, i.v.), and long-lasting inhibition of platelet aggregation was observed upon oral administration of 9 (3 mg/kg) to guinea pigs. On the other hand, the activity of 26 disappeared within 1 h after a dose of 1 mg/kg (i.v.). Compound 9 may therefore be useful in the clinical treatment of arterial thrombotic diseases.
Sugihara
H
H
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan. Sugihara_Hirosada@takeda.co.jp
Fukushi
H
H
Miyawaki
T
T
Imai
Y
Y
Terashita
Z
Z
Kawamura
M
M
Fujisawa
Y
Y
Kita
S
S
D000818:Animals; D015195:Drug Design; D005340:Fibrinogen / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D015394:Molecular Structure; D009842:Oligopeptides; D010879:Piperazines / 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* / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D013329:Structure-Activity Relationship
D006146:Guanidines; D009842:Oligopeptides; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011719:Pyrazines; C084961:arginyl-glycyl-aspartyl-phenylalanine; D005340:Fibrinogen; C099142:TAK 029