Parlow John J, Burney Mary W, Case Brenda L, Girard Thomas J, Hall Kerri A, Hiebsch Ronald R, Huff Rita M, Lachance Rhonda M, Mischke Deborah A, Rapp Stephen R, Woerndle Rhonda S, Ennis Michael D
Department of Medicinal Chemistry, Pfizer Global Research & Development, Chesterfield, MO 63017, USA.
Bioorg Med Chem Lett. 2009 Aug 15;19(16):4657-63. doi: 10.1016/j.bmcl.2009.06.075. Epub 2009 Jun 25.
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 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 22J with good human PRP potency, selectivity, in vivo efficacy and oral bioavailability.
聚合物辅助溶液相（PASP）平行库合成法被用于发现一种哌嗪基 - 谷氨酸 - 吡啶作为P2Y(12)拮抗剂。对该先导化合物的开发得到了在人富血小板血浆（PRP）试验中对血小板聚集具有优异抑制作用的化合物。对其药代动力学和物理化学性质进行了优化，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22J，其在人PRP中具有良好的效力、选择性、体内疗效和口服生物利用度。
