RWJ-38063

A chemical feature based pharmacophore model was developed for alpha(1A)-adrenoceptor antagonists by HypoGen module implemented in catalyst software package. The best scoring pharmacophore hypothesis, Hypo1, consisted of four important chemical features (one positive ion, one hydrogen-bond donor, one aromatic ring, and one hydrophobic group). The results of our study provide a valuable tool in designing new leads with desired biological activity by virtual screening.

The development of α_1a-adrenergic receptor (AR) subtype-selective antagonists is likely to result in uroselective agents that effectively treat benign prostatic hyperplasia (BPH) symptoms without causing undesirable side effects that may be due to vascular α₁-AR blockade.The properties of four aryl piperazine compounds (RWJ-38063, RWJ-68141, RWJ-68157, and RWJ-69736) are described in this report and compared with the properties of tamsulosin, an α₁-AR antagonist that is used in the treatment of BPH.Radioligand binding studies show that all four RWJ compounds have significantly higher affinity for the α_1a-AR subtype than for the α_1b or α_1d subtype and display a higher level of receptor subtype selectivity than tamsulosin.The RWJ compounds were more potent in inhibiting (±)-norepinephrine-induced contractions of isolated rat prostate tissue than those of isolated rat aorta tissue, whereas tamsulosin had the reversed tissue selectivity.RWJ-38063 and RWJ-69736 had the highest potency in the isolated prostate tissue assays of the four RWJ compounds, with pK_B values of 8.24 and 9.26, resp., and were 319- and 100-fold more potent in their effects on isolated prostate tissue than aorta tissue.The in vivo uroselectivities of RWJ-38063, RWJ-69736, and tamsulosin were examined in anesthetized dogs.Both RWJ compounds suppressed the intraurethral pressure response to phenylephrine to a greater extent than the mean arterial pressure response; however, RWJ-69736 also caused a marked transient rise in heart rate.Although less potent, RWJ-38063 and RWJ-69736 were notably more uroselective than tamsulosin in this canine model.