Borthwick Alan D, Davies Dave E, Exall Anne M, Hatley Richard J D, Hughes Jennifer A, Irving Wendy R, Livermore David G, Sollis Steve L, Nerozzi Fabrizio, Valko Klara L, Allen Michael J, Perren Marion, Shabbir Shalia S, Woollard Patrick M, Price Mark A
Department of Medicinal Chemistry, Cardiovascular and Urogenital Centre of Excellence for Drug Discovery, Stevenage, UK.
J Med Chem. 2006 Jul 13;49(14):4159-70. doi: 10.1021/jm060073e.
A short, efficient, and highly stereoselective synthesis of a series of (3R,6R,7R)-2,5-diketopiperazine oxytocin antagonists and their pharmacokinetics in rat and dog is described. Prediction of the estimated human oral absorption (EHOA) using measured lipophilicity (CHI log D) and calculated size (cMR) has allowed us to rank various 2,5-diketopiperazine templates and enabled us to focus effort on those templates with the greatest chance of high bioavailability in humans. This rapidly led to the 2',4'-difluorophenyl-dimethylamide 25 and the benzofuran 4 with high levels of potency (pK(i)) and good bioavailability in the rat and dog. Dimethylamide 25 is more potent (>20-fold) than 4 in vivo and has a high degree of selectivity toward the vasopressin receptors, >10,000 for hV1a/hV1b and approximately 500 for hV2. It has a good Cyp450 profile with no time dependent inhibition and was negative in the genotoxicity screens with a satisfactory oral safety profile in rats.
描述了一系列(3R,6R,7R)-2,5-二酮哌嗪催产素拮抗剂的简短、高效且高度立体选择性的合成及其在大鼠和犬体内的药代动力学。利用测得的亲脂性(CHI log D)和计算得出的分子大小(cMR)预测人体口服吸收估计值(EHOA)，使我们能够对各种2,5-二酮哌嗪模板进行排名，并使我们能够将精力集中在那些在人体中具有最高生物利用度可能性的模板上。这迅速导致了在大鼠和犬体内具有高活性(pK(i))和良好生物利用度的2',4'-二氟苯基二甲基酰胺25和苯并呋喃4。二甲基酰胺25在体内比4更具活性(>20倍)，并且对血管加压素受体具有高度选择性，对hV1a/hV1b大于10,000，对hV2约为500。它具有良好的细胞色素P450谱，无时间依赖性抑制，在遗传毒性筛选中呈阴性，在大鼠中口服安全性良好。
