Xiaoming Zhou

4-(2-pyridyl)piperazine-1-carboxamides: potent vanilloid receptor 1 antagonists.

A series of 4-(2-pyridyl)piperazine-1-carboxamide analogues based on the lead compound 1 was synthesized and evaluated for VR1 antagonist activity in capsaicin-induced (CAP) and pH (5.5)-induced (pH) FLIPR assays in a rat VR1-expressing HEK293 cell line. Potent VR1 antagonists were identified through SAR studies. From these studies, 18 was found to be very potent in the in vitro assay [IC(50)=4.8 nM (pH) and 35 nM (CAP)] and orally available in rat (F%=15.1).

Solid-phase synthesis of isoindolines via a rhodium-catalyzed [2+2+2] cycloaddition

Abstract An efficient solid-phase synthesis of isoindolines is reported. The key reaction step is a rhodium-catalyzed [2+2+2] cycloaddition of alkynes to give isoindolines in good yield.

Structure-activity relationship studies and discovery of a potent transient receptor potential vanilloid (TRPV1) antagonist 4-[3-chloro-5-[(1S)-1,2-dihydroxyethyl]-2-pyridyl]-N-[5-(trifluoromethyl)-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxamide (V116517) as a clinical candidate for pain management.

A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expressing human TRPV1. The most potent of these TRPV1 antagonists were further characterized in pharmacokinetic, efficacy, and body temperature studies. On the basis of its pharmacokinetic, in vivo efficacy, safety, and toxicological properties, compound 37 was selected for further evaluation in human clinical trials.

Solid-phase synthesis of 3,4-dihydro-2(1H)-quinazolinones and 3,4-dihydro-1H-quinazolin-2-thiones

The solid-phase synthesis of 3,4-dihydro-2(1H)-quinazolinones and 3,4-dihydro-1H-quinazolin-2-thiones is described. Starting from Rink resin, acylation with 4-bromomethyl-3-nitrobenzoic acid and amination with primary amines, reduction with tin chloride and cyclization, the desired 3,4-dihydro-2(1H)-quinazolinones and 3,4-dihydro-1H-quinazolin-2-thiones have been synthesized in good yield and high purity.