4 research outputs found
Carbohydrate-derived iminium salt organocatalysts for the asymmetric epoxidation of alkenes
A new family of carbohydrate-based dihydroisoquinolinium salts has been prepared and tested for potential as asymmetric catalysts for the epoxidation of unfunctionalized alkene substrates, providing up to 57% ee in the product epoxides
Development of a Series of Kynurenine 3-Monooxygenase Inhibitors Leading to a Clinical Candidate for the Treatment of Acute Pancreatitis
Recently,
we reported a novel role for KMO in the pathogenesis
of acute pancreatitis (AP). A number of inhibitors of kynurenine 3-monooxygenase
(KMO) have previously been described as potential treatments for neurodegenerative
conditions and particularly for Huntington’s disease. However,
the inhibitors reported to date have insufficient aqueous solubility
relative to their cellular potency to be compatible with the intravenous
(iv) dosing route required in AP. We have identified and optimized
a novel series of high affinity KMO inhibitors with favorable physicochemical
properties. The leading example is exquisitely selective, has low
clearance in two species, prevents lung and kidney damage in a rat
model of acute pancreatitis, and is progressing into preclinical development
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
Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3‑Amino-4-pyridine Carboxylate Derivatives
Optimization
of KDM6B (JMJD3) HTS hit <b>12</b> led to the
identification of 3-((furan-2-ylmethyl)Âamino)Âpyridine-4-carboxylic
acid <b>34</b> and 3-(((3-methylthiophen-2-yl)Âmethyl)Âamino)Âpyridine-4-carboxylic
acid <b>39</b> that are inhibitors of the KDM4 (JMJD2) family
of histone lysine demethylases. Compounds <b>34</b> and <b>39</b> possess activity, IC<sub>50</sub> ≤ 100 nM, in KDM4
family biochemical (RFMS) assays with ≥50-fold selectivity
against KDM6B and activity in a mechanistic KDM4C cell imaging assay
(IC<sub>50</sub> = 6–8 μM). Compounds <b>34</b> and <b>39</b> are also potent inhibitors of KDM5C (JARID1C)
(RFMS IC<sub>50</sub> = 100–125 nM)