A first-in-human, double-blind, placebo-controlled, randomized, dose escalation study of DWP05195, a novel TRPV1 antagonist, in healthy volunteers.

OBJECTIVES: DWP05195 is a transient receptor potential vanilloid 1 (TRPV1) antagonist developed for managing pain. The purpose of this study was to evaluate the pharmacodynamics pharmacokinetics, safety, and tolerability of DWP05195 in healthy subjects. This was a first-in-human randomized, double-blinded, placebo-controlled, dose escalation study. SUBJECTS AND METHODS: DWP05195 or placebo was administered as a single dose of 10-600 mg in the single-dose study and as 100-400 mg once daily for 8 days in the multiple-dose studies. Each study group consisted of 10 subjects (study drug-to-placebo ratio was 8:2). For pharmacodynamics assessment, the heat pain threshold (HPtr), heat pain tolerance (HPtol), perfusion intensity, and flare area ratio of cutaneous blood flow were measured. Safety and tolerability were evaluated throughout the study. RESULTS: The maximum plasma concentrations and area under the plasma concentration-time curve from zero to the last measurable time dose-dependently increased. HPtr and HPtol tended to increase more after DWP05195 administration than after placebo administration. HPtr and HPtol tended to dose-dependently increase after administration of DWP05195. Cutaneous blood flow was reduced as the dose of DWP05195 increased during the multiple-dose study. DWP05195 was well tolerated up to 600 and 400 mg single- and multiple-dose administrations, respectively. CONCLUSION: The pharmacological activity of DWP05195, measured using HPtr and HPtol, increased as expected in a dose-dependent manner owing to increased systemic exposure, indicating that DWP05195 can be used as a TRPV1 antagonist for pain management.

Regioselective and diastereoselective amination with use of chlorosulfonyl isocyanate: a short and efficient synthesis of (-)-cytoxazone.

The total synthesis of (-)-cytoxazone 1 was achieved in six linear steps (34% overall yield) from p-anisaldehyde. The key steps in this route are the regioselective and stereoselective introduction of a N-protected amine group, using the CSI reaction of the anti-1,2-dimethyl ether 3, and the subsequent regioselective cyclization of the N-protected amino diol 13 to give the 2-oxazolidinone unit of (-)-cytoxazone 1. [reaction: see text]

Diastereoselective synthesis of unsaturated 1,4-amino alcohols as a biologically important moiety.

The diastereoselective synthesis of unsaturated 1.4-amino alcohols can be achieved using chial allylic ethers with a hydroxyl group attached to the pi-system and chlorosulfonyl isocyanate. The enantioselectivity of the CSI reaction with the chiral allylic and benzylic ethers was examined in various solvents and temperatures. Based on these results, it was proposed that the CSI reaction is a competitive reaction of a SNi (retention) and a SN1 mechanism (racemization) according to the stability of the carbocation intermediate. This means that there is a greater proportion of retention with the less stable the carbocation intermediate and vise versa.

Mechanism studies on the CSI reaction with allyl ethers by varying p-substituent.

We examined the effect of p-substituents in p-substituted cinnamyl methyl ethers and 1-(p-substituted phenyl)allyl methyl ethers with CSI, and confirmed that the CSI reaction of allyl ethers (p-substituted ethers) is a competitive reaction of S(N)i and S(N)1 mechanism according to the stability of the carbocation. And, the only terminal allylic amine was obtained through the migration reaction in thermodynamic reaction condition.

Regioselective and diastereoselective allylic amination using chlorosulfonyl isocyanate. A novel asymmetric synthesis of unsaturated aromatic 1,2-amino alcohols.

The diastereoselective synthesis of unsaturated aromatic 1,2-amino alcohols can be achieved on an epimeric mixture of optically active allylic ethers having a hydroxyl group attached to an allylic chiral center to the pi-system using chlorosulfonyl isocyanate. These reactions produced the unsaturated anti-1,2-amino alcohols either exclusively or predominantly only for aromatic derivatives. The anti-selectivity may be explained by the Cieplak electronic model during the conversion from ethers to carbamates.