KMD-3213, a uroselective and long-acting alpha(1a)-adrenoceptor antagonist, tested in a novel rat model

KMD-3213, an alpha(1a)-adrenoceptor (AR) antagonist, is under development for the treatment of urinary outlet obstruction in patients with benign prostatic hypertrophy. In the present study, we developed a rat model to investigate simply the effects of alpha(1)-AR antagonists on the intraurethral pressure (IUP) response to phenylephrine. Using this model, inhibitory effects of both i.v. and intraduodenally administered KMD-3213 on the IUP response were evaluated and compared to those of other reference compounds, including prazosin and tamsulosin. In addition, the hypotensive effects of these compounds were estimated to evaluate uroselectivity. Intravenously administered alpha(1)-AR antagonists tested, including KMD-3213, potently inhibited the IUP response in a dose-dependent manner. Although the higher doses of those compounds almost completely inhibited the IUP response, yohimbine failed to inhibit the response. When the in vivo potencies of those compounds on IUP response were correlated with their affinities for the human or animal recombinant alpha(1)-AR subtypes, alpha(1a)-AR gave the best correlation. In this model, KMD-3213 had greater uroselectivity than any other compounds examined, by both i.v. and intraduodenal routes. Moreover, 12, 18, and 24 h after the oral administration of KMD-3213, a dose-dependent inhibition of the IUP response was found, whereas the effect of tamsulosin disappeared at 18 h after the oral administration. These data indicate that KMD-3213 is a highly uroselective alpha(1)-AR antagonist with a longer duration of action. In addition, this model is useful for not only estimation of uroselectivity but also some part of the administration, distribution, metabolism, and excretion of many compounds to discover uroselective compounds.