2 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
Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy
Inhibition of Itk potentially constitutes
a novel, nonsteroidal
treatment for asthma and other T-cell mediated diseases. In-house
kinase cross-screening resulted in the identification of an aminopyrazole-based
series of Itk inhibitors. Initial work on this series highlighted
selectivity issues with several other kinases, particularly AurA and
AurB. A template-hopping strategy was used to identify a series of
aminobenzothiazole Itk inhibitors, which utilized an inherently more
selective hinge binding motif. Crystallography and modeling were used
to rationalize the observed selectivity. Initial exploration of the
SAR around this series identified potent Itk inhibitors in both enzyme
and cellular assays