Discovery of an orally active non-peptide fibrinogen receptor antagonist based on the hydantoin scaffold.
Antagonists of the platelet fibrinogen receptor (GP IIb/IIIa receptor) are expected to be a promising new class of antithrombotic agents. The binding of fibrinogen to the fibrinogen receptor depends on an Arg-Gly-Asp-Ser (RGDS) tetrapeptide recognition motif. Structural modifications of the RGDS lead have led to the discovery of a non-peptide RGD mimetic GP IIb/IIIa antagonist 44 (S 1197). Compound 44 inhibited, in a dose dependent and reversible manner, human and dog platelet aggregation as well as 125I-fibrinogen binding to ADP-activated human gel filtered platelets and isolated GP IIb/IIIa with K(i) values of 9 nM and 0.17 nM, respectively. A pharmacophore mapping procedure with QXP and a 3D-QSAR analysis applying the GRID/GOLPE methodology yielded a stable, rather predictive model and revealed structural features which are important for binding. Hydrophobic substitutions both at the hydantoin nucleus and at the C-terminus increase the affinity toward the fibrinogen receptor. The crystalline ethyl ester prodrug 48 (HMR 1794) is an orally active antithrombotic agent which is a promising drug candidate for the treatment of thrombotic diseases in humans.
Stilz
H U
HU
Chemistry and DG Cardiovascular Agents, Aventis Pharma AG, D-65926 Frankfurt am Main, Germany. Ulrich.Stilz@aventis.com
Guba
W
W
Jablonka
B
B
Just
M
M
Klingler
O
O
König
W
W
Wehner
V
V
Zoller
G
G
D000284:Administration, Oral; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D004285:Dogs; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007231:Infant, Newborn; D008958:Models, Molecular; 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; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism
D006827:Hydantoins; D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011355:Prodrugs; D011422:Propionates; C424910:ethyl 3-(2-(4-(4-aminoiminomethylphenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionate; D005340:Fibrinogen