New, Potent, and Selective Peptidic Oxytocin Receptor Agonists

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 V<sub>2</sub> receptor mediated antidiuresis. We have designed a series of potent oxytocin analogues containing <i>N</i>-alkylglycines in position 7 with excellent selectivity versus the related V<sub>1a</sub>, V<sub>1b</sub>, and V<sub>2</sub> vasopressin receptors and short half-life: agonists <b>31</b> ([2-ThiMeGly<sup>7</sup>]­dOT), <b>47</b> (carba-6-[Phe<sup>2</sup>,BuGly<sup>7</sup>]­dOT), <b>55</b> (carba-6-[3-MeBzlGly<sup>7</sup>]­dOT), and <b>57</b> (carba-1-[4-FBzlGly<sup>7</sup>]­dOT) have EC<sub>50</sub> values at hOTR < 0.1 nM, selectivity ratios versus related human vasopressin receptors of >2000, IC<sub>50</sub> at hV<sub>1a</sub>R > 500 nM, and total clearance in rats in the range of 60–80 mL min<sup>–1</sup> kg<sup>–1</sup>. Compound <b>57</b> (FE 202767) is currently in clinical development for the treatment of preterm mothers requiring lactation support.