Blockade of the P2Y1 receptor is important to the treatment of thrombosis with potentially improved safety margins compared with P2Y12 receptor antagonists. Investigation of a series of urea surrogates of the diaryl urea lead 3 led to the discovery of 2-amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y1 receptor antagonists, among which compound 5a was the most potent and the first non-urea analog with platelet aggregation (PA) IC50 less than 0.5 μM with 10 μM ADP. Several 2-amino-1,3,4-thiadiazole analogs such as 5b and 5f had a more favorable pharmacokinetic profile, such as higher Ctrough, lower Cl, smaller Vdss, and similar bioavailability compared with 3.
Keywords: 2-Amino-1,3,4-thiadiazoles; Antiplatelet; P2Y(1) receptor antagonist; Structure–activity relationship (SAR); Urea mimetics.
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