18 research outputs found
Identification of potent and selective oxytocin antagonists. Part 1:indole and benzofuran derivatives
Studies to discover novel, potent and selective oxytocin antagonists are reported. Combinatorial libraries designed to find novel replacements of fragments of oxytocin antagonist L-371,257, identified pyrimidine, thiazole, indole and benzofuran as potential alternatives to the benzoic acid moiety of L-371,257. Additional investigations identified indole and benzofuran derivatives with potent oxytocin antagonist activity
Identification of potent and selective oxytocin antagonists. Part 2: further investigation of benzofuran derivatives
The paper covers continuing efforts to discover novel, potent and selective oxytocin antagonists. Further benzofuran derivatives with potent oxytocin antagonist activity and good pharmacokinetic parameters are reported. Efforts to improve the in vivo activity of the series are described
Integration of Lead Optimization with Crystallography for a Membrane-Bound Ion Channel Target: Discovery of a New Class of AMPA Receptor Positive Allosteric Modulators
A novel series of AMPAR positive modulators is described that were identified by high throughput screening. The molecules of the series have been optimized from a high quality starting point hit to afford excellent developability, tolerability, and efficacy profiles, leading to identification of a clinical candidate. Unusually for an ion channel target, this optimization was integrated with regular generation of ligand-bound crystal structures and uncovered a novel chemotype with a unique and highly conserved mode of interaction via a trifluoromethyl group
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