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 f or the treatment of urinary outlet obstruction in patients with benign pros tatic hypertrophy. In the present study, we developed a rat model to invest igate simply the effects of alpha(1)-AR antagonists on the intraurethral pr essure (IUP) response to phenylephrine. Using this model, inhibitory effect s of both i.v. and intraduodenally administered KMD-3213 on the IUP respons e were evaluated and compared to those of other reference compounds, includ ing prazosin and tamsulosin. In addition, the hypotensive effects of these compounds were estimated to evaluate uroselectivity. Intravenously administ ered 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 fai led to inhibit the response. When the in vivo potencies of those compounds on IUP response were correlated with their affinities for the human or anim al recombinant alpha(1)-AR subtypes, alpha(1a)-AR gave the best correlation . In this model, KMD-3213 had greater uroselectivity than any other compoun ds examined, by both i.v. and intraduodenal routes. Moreover, 12, 18, and 2 4 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 i s a highly uroselective alpha(1)-AR antagonist with a longer duration of ac tion. In addition, this model is useful for not only estimation of uroselec tivity but also some part of the administration, distribution, metabolism, and excretion of many compounds to discover uroselective compounds.