The design, synthesis, and pharmacological evaluation of L-734,217, a potent, low-molecular weight, orally active fibrinogen receptor antagonist, is reported. A strategy for producing low-molecular weight inhibitors from the peptide c-[(Ac)CRGDC] A, previously reported from these laboratories, is outlined. This strategy combines a retrodesign analysis of the conformationally defined cyclic peptide A with stereochemical information present in the arginine-glycine-aspartic acid (RGD) tripeptide sequence, culminating with the discovery of L-734,217. L-734,217 inhibited the aggregation of human, dog, and chimpanzee platelets at concentrations below 100 nM and was found to be > 15000-fold less effective at inhibiting the attachment of human umbilical vein endothelial cells to fibrinogen, fibronectin, and vitronectin than it was at inhibiting the aggregation of platelets. L-734,217 showed significant ex vivo antiplatelet activity following oral administration in dogs and chimpanzees at doses of 1.0 and 2.0 mg/kg, respectively, and has been selected as a clinical candidate for development as an antithrombotic agent.
5-Formyl-2'-deoxyuridine (2a), an effective inhibitor of herpes simplex virus type 1 or 2 (HSV-1, HSV-2) and vaccinia virus, was converted to the oxime (3a) and dithiolane (4a) derivatives. The oxime (3a) was equally as potent as the formyl compound against HSV-1, but one-fifth as active against HSV-2, 100 times less effective against vaccinia, and 25 times less toxic for the host cells. In addition, compound 3a was about 10 times less active than 2a in inhibiting thymidylate synthetase in vivo (as reflected by a differential inhibition of dThd and dUrd incorporation into host cell DNA). The dithiolane (4a) did not exert an appreciable effect on either virus multiplication or dThd or dUrd incorporation, nor was it cytotoxic. All these compounds as their 5'-phosphate derivatives were potent in vitro inhibitors of thymidylate synthetase (Lactobacillus casei). The inhibition was competitive with substrate with Ki/Km ratios of 0.05 for the formyl 2b, 0.5 for the oxime 3b, and 0.2 for the dithiolane 4b. Thus, 3b was 10 times less active than 2b as an in vitro inhibitor of thymidylate synthetase, which appears to corroborate the in vivo findings.
5-(alpha-Bromoacetyl)-2'-deoxyuridine 5'-phosphate (1) is an active-site-directed irreversible inhibitor of thymidylate synthetase from Lactobacillus casei. Analysis of the rate of inactivation of the enzyme in the presence of substrate confirmed the intermediate formation of a reversible enzyme-inhibitor complex.
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