Ferring Research Institute Inc. , 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
J Med Chem. 2014 Jun 26;57(12):5306-17. doi: 10.1021/jm500365s. Epub 2014 Jun 12.
Mothers of preterm babies frequently have difficulty establishing or maintaining lactation, thought to be due to interference with the milk ejection reflex. Administration of exogenous oxytocin can produce alveolar contraction and adequate breast emptying resulting in establishment of successful lactation. The natural hormone oxytocin is not receptor-selective and may cause hyponatremia via V2 receptor mediated antidiuresis. We have designed a series of potent oxytocin analogues containing N-alkylglycines in position 7 with excellent selectivity versus the related V1a, V1b, and V2 vasopressin receptors and short half-life: agonists 31 ([2-ThiMeGly(7)]dOT), 47 (carba-6-[Phe(2),BuGly(7)]dOT), 55 (carba-6-[3-MeBzlGly(7)]dOT), and 57 (carba-1-[4-FBzlGly(7)]dOT) have EC50 values at hOTR < 0.1 nM, selectivity ratios versus related human vasopressin receptors of >2000, IC50 at hV1aR > 500 nM, and total clearance in rats in the range of 60-80 mL min(-1) kg(-1). Compound 57 (FE 202767) is currently in clinical development for the treatment of preterm mothers requiring lactation support.
早产儿的母亲经常难以建立或维持哺乳，据认为这是由于泌乳反射受到干扰。外源性催产素的给药可以产生肺泡收缩和充分排空乳房，从而成功建立哺乳。天然激素催产素不是受体选择性的，并且可能通过 V2 受体介导的抗利尿作用引起低钠血症。我们设计了一系列含有 7 位 N-烷基甘氨酸的强效催产素类似物，对相关的 V1a、V1b 和 V2 血管加压素受体具有优异的选择性和短半衰期：激动剂 31([2-ThiMeGly(7)]dOT)、47(卡巴-6-[Phe(2),BuGly(7)]dOT)、55(卡巴-6-[3-MeBzlGly(7)]dOT)和 57(卡巴-1-[4-FBzlGly(7)]dOT)在 hOTR 处的 EC50 值<0.1 nM，对相关人血管加压素受体的选择性比值>2000，在 hV1aR 处的 IC50>500 nM，在大鼠中的总清除率在 60-80 mL min(-1)kg(-1)范围内。化合物 57(FE 202767)目前正在临床开发中，用于治疗需要哺乳支持的早产儿母亲。
