Pyridyl-2,5-Diketopiperazines as Potent, Selective, and Orally Bioavailable Oxytocin Antagonists: Synthesis, Pharmacokinetics, and In Vivo Potency

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• 作者：Alan D. Borthwick ; John Liddle ; Dave E. Davies ; Anne M. Exall ; Christopher Hamlett ; Deirdre M. Hickey ; Andrew M. Mason ; Ian E. D. Smith ; Fabrizio Nerozzi ; Simon Peace ; Derek Pollard ; Steve L. Sollis ; Michael J. Allen ; Patrick M. Woollard ; Mark A. Pullen ; Timothy D. Westfall ; Dinesh J. Stanislaus
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：January 26, 2012
• 年：2012
• 卷：55
• 期：2
• 页码：783-796
• 全文大小：808K
• 年卷期：v.55,no.2(January 26, 2012)
• ISSN：1520-4804

文摘

A six-stage stereoselective synthesis of indanyl-7-(3鈥?pyridyl)-(3R,6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3鈥?pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pK_i > 9.0) with good aqueous solubility. Evaluation of the pharmacokinetic profile in the rat, dog, and cynomolgus monkey of those derivatives with low cynomolgus monkey and human intrinsic clearance gave 2鈥?6鈥?dimethyl-3鈥?pyridyl R-sec-butyl morpholine amide Epelsiban (69), a highly potent oxytocin antagonist (pK_i = 9.9) with >31000-fold selectivity over all three human vasopressin receptors hV1aR, hV2R, and hV1bR, with no significant P450 inhibition. Epelsiban has low levels of intrinsic clearance against the microsomes of four species, good bioavailability (55%) and comparable potency to atosiban in the rat, but is 100-fold more potent than the latter in vitro and was negative in the genotoxicity screens with a satisfactory oral safety profile in female rats.