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Background: KMD-3213 is an a 1A -adrenoceptor-selective antagonist currently being developed for the treatment of urinary outlet obstruction in patients with benign prostatic hyperplasia. In the present study, the uroselectivity of KMD-3213 was evaluated and compared with that of prazosin and tamsulosin in a decerebrate dog model. Methods: Intercollicular decerebration was carried out in male mongrel dogs under anesthesia. The inhibitory effects of intravenously and intraduodenally administered compounds on the increase in intraurethral pressure (IUP) induced by electrical stimulation of the hypogastric nerve were estimated. Systemic blood pressure was measured simultaneously. Results:The a 1 -antagonists tested produced a dose-dependent inhibition of the induced IUP response and decreased mean blood pressure (MBP). The ID 50 of KMD-3213, tamsulosin and prazosin for IUP (dose required to inhibit the increase in IUP by 50%) was 3.15, 1.73 and 11.8 mg/kg i.v., respectively, and the ED 20 for the hypotensive effect (dose required to reduce MBP by 20%) was 8.03, 0.59 and 2.46 mg/kg i.v., respectively. The data indicate that uroselectivity (ED 20 /ID 50 ) of KMD-3213 is 12-and 7.5-fold higher than that of prazosin and tamsulosin, respectively. When the drugs were administered intraduodenally, KMD-3213 was sufficiently absorbed from the digestive tract and continued to demonstrate at least 3.8-fold higher uroselectivity than tamsulosin. Conclusion: Based on these findings, KMD-3213 appears to be an effective orally active compound for decreasing urethral resistance during micturition that does not induce any negative cardiovascular effects in patients with benign prostatic hyperplasia.

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ABSTRACT-KMD-3213((-)-1-(3-hydroxypropyl)-5-((2R)-2-{[2-({2-[(2,2,2-trifluoroethyl)oxy]phenyl} oxy)ethyl]amino}propyl)-2,3-dihydro-1H-indole-7-carboxamide), an =1A-adrenoceptor antagonist with potency similar to that of tamsulosin, is under development for the treatment of bladder outlet obstruction in patients with benign prostatic hypertrophy. In the present study, we investigated the effects of KMD-3213 on the tilt-induced blood pressure response in anesthetized normotensive rats. Male normotensive SpragueDawley rats were placed in the supine position on a board under cocktail anesthetization (a-chloralose, urethane and sodium pentobarbital). The arterial blood pressure was measured from the carotid artery. The animals were given consistent 45° head-up tilt from the horizontal position, following the transient decrease in the blood pressure, and then recovery of the blood pressure to the normal level. Significant orthostatic hypotension was seen with intravenous administration of both prazosin and tamsulosin at doses over 3 mg /kg, and these drugs completely blocked the tilt-induced blood pressure responses at 30 mg/kg. On the other hand, these responses were still retained when KMD-3213 was administered intravenously at a dose up to 75 mg/kg of KMD-3213. Moreover, KMD-3213 showed the highest uroselectivity of the test drugs. These results indicate that KMD-3213 is not likely to induce orthostatic hypotension and would be a useful compound for the treatment of urinary outlet obstruction in patients with benign prostatic hyperplasia.