Key result
Compound 47s, a piperazinyl glutamate pyridine, demonstrated good human platelet rich plasma potency, selectivity, in vivo efficacy, and oral bioavailability as a P2Y12 antagonist.
Compound 47s was identified as a potent, orally bioavailable P2Y12 antagonist for the inhibition of platelet aggregation, warranting further preclinical evaluation.
Supports further preclinical development of 47s; leaves open clinical translation as a P2Y12 antagonist.
Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl glutamate pyridine as a P2Y(12) antagonist. Exploitation of this lead provided compounds with excellent inhibition of platelet aggregation as measured in a human platelet rich plasma (PRP) assay. Pharmacokinetic and physiochemical properties were optimized through modifications at the 4-position of the pyridine ring and the terminal nitrogen of the piperazine ring, leading to compound (4S)-4-[({4-[4-(methoxymethyl)piperidin-1-yl]-6-phenylpyridin-2-yl}carbonyl)amino]-5-oxo-5-{4-[(pentyloxy)carbonyl]piperazin-1-yl}pentanoic acid 47s with good human PRP potency, selectivity, in vivo efficacy, and oral bioavailability. Compound 47s was selected for further preclinical evaluations.
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Parlow et al. (2010) studied Platelet aggregation. Compound 47s (piperazinyl glutamate pyridine) was evaluated on Inhibition of platelet aggregation and pharmacokinetic properties. Compound 47s, a piperazinyl glutamate pyridine, demonstrated good human platelet rich plasma potency, selectivity, in vivo efficacy, and oral bioavailability as a P2Y12 antagonist.
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