1 research outputs found
Pyridyl-2,5-Diketopiperazines as Potent, Selective, and Orally Bioavailable Oxytocin Antagonists: Synthesis, Pharmacokinetics, and In Vivo Potency
A six-stage stereoselective synthesis of indanyl-7-(3′-pyridyl)-(3<i>R</i>,6<i>R</i>,7<i>R</i>)-2,5-diketopiperazines
oxytocin antagonists from indene is described. SAR studies involving
mono- and disubstitution in the 3′-pyridyl ring and variation
of the 3-isobutyl group gave potent compounds (p<i>K</i><sub>i</sub> > 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′,6′-dimethyl-3′-pyridyl <i>R</i>-<i>sec</i>-butyl morpholine amide Epelsiban
(<b>69</b>), a highly potent oxytocin antagonist (p<i>K</i><sub>i</sub> = 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