K-685, a TRPV1 antagonist, blocks PKC-sensitized TRPV1 activation and improves the inflammatory pain in a rat complete Freund's adjuvant model.

Transient receptor potential vanilloid 1 (TRPV1) is a Ca(2+)-permeable non-selective cation channel that transmits pain signals. TRPV1 is activated by multiple stimuli such as capsaicin, acid, and heat. During inflammation, TRPV1 is reported to be sensitized by protein kinase C (PKC) in dorsal root ganglia (DRG) neurons, which leads to reduction in the threshold of the temperature for TRPV1 activation to body temperature.

Discovery of novel 5,5-diarylpentadienamides as orally available transient receptor potential vanilloid 1 (TRPV1) antagonists.

We have developed a novel and potent chemical series of 5,5-diphenylpentadienamides for targeting TRPV1 in vitro and in vivo. In this investigation, we examined a variety of replacements for the 5-position of dienamides with the goal of addressing issues related to pharmacokinetics. Our data suggest that substitution with alkoxy groups on the phenyl ring at the 5-position increases their ability to penetrate the blood-brain barrier.

Synthetic studies on selective adenosine A2A receptor antagonists. Part II: synthesis and structure-activity relationships of novel benzofuran derivatives.

Based on the previously reported lead compound, a series of benzofuran derivatives were prepared to study their antagonistic activities to A(2A) receptor. The replacement of the phenyl group at the 4-position with a heterocyclic ring improved the PK profile and aqueous solubility. From these studies, we discovered a potent new A(2A) antagonist, 12a, which has both a good oral bioavailability and in vivo efficacy on motor disability in MPTP-treated common marmosets.

Synthetic studies on selective adenosine A2A receptor antagonists: synthesis and structure-activity relationships of novel benzofuran derivatives.

A series of benzofuran derivatives were prepared to study their antagonistic activities to the A(2A) receptor. Replacement of the ester group of the lead compound 1 with phenyl ring improved the PK profile, while modifications of the amide moiety showed enhanced antagonistic activity. From these studies, compounds 13c, 13f, and 24a showed good potency in vitro and were identified as novel A(2A) receptor antagonists suitable for oral activity evaluation in animal models of catalepsy.

Synthetic study of VLA-4/VCAM-1 inhibitors: synthesis and structure-activity relationship of piperazinylphenylalanine derivatives.

To improve the poor pharmacokinetic characteristics of VLA-4 inhibitors, novel piperazinylphenylalanine derivatives were designed. This structure is expected to improve physicochemical properties by increasing overall basicity. By changing components at the 4-position of piperazine and the terminal group of the amido bond, 12t was found to be the most potent of this series of compounds.