Department of Medicinal Chemistry, Pfizer Global Research & Development, 700 Chesterfield Parkway West, Chesterfield, Missouri 63017, USA.
J Med Chem. 2010 Mar 11;53(5):2010-37. doi: 10.1021/jm901518t.
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.
采用聚合物辅助的溶液相（PASP）平行库合成法发现了一种哌嗪基谷氨酸吡啶作为 P2Y（12）拮抗剂。对该先导化合物的开发提供了具有优异的血小板聚集抑制作用的化合物，如在人富含血小板的血浆（PRP）测定中所测量的。通过对吡啶环的 4 位和哌嗪环的末端氮进行修饰，优化了药代动力学和物理化学性质，得到了化合物（4S）-4-[({4-[4-（甲氧基甲基）哌啶-1-基]-6-苯基吡啶-2-基}羰基)氨基]-5-氧代-5-{4-[(戊氧基)羰基]哌嗪-1-基}戊酸 47s，其具有良好的人 PRP 效力、选择性、体内疗效和口服生物利用度。选择化合物 47s 进行进一步的临床前评估。
