Preclinical pharmacology of fiduxosin, a novel α1-adrenoceptor antagonist with uroselective properties

Benign prostatic hyperplasia (BPH), common in aging males, is often treated with a,adrenoceptor antagonists. To minimize hypotensive and other side effects, compounds with selective antagonist activity at alpha(1A)- and alpha(1D)- (compared with alpha(1B)-) adrenoceptors were evaluated that would block lower urinary tract alpha(1)-adrenoceptors in preference to cardiovascular alpha(1B)-adrenoceptors. Fiduxosin (3-[4-((3aR,9bR)-cis-9-methoxyl,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl]8-phenyl-pyrazino[2',3':4,5] thieno-[3,2-d]pyrimidine-2,4(1H,3H)-dione; ABT-980) was tested in radioligand binding assays, isolated tissue bioassays, intraurethral pressure (IUP) tests in isoflurane-anesthetized dogs, and blood pressure analyses in spontaneously hypertensive rats (SHR). Fiduxosin had higher affinity for cloned human alpha(1a)- (0.16 nM) and alpha(1d)-adrenoceptors (0.92 nM) in radioligand binding studies compared with alpha(1b)-adrenoceptors (25 nM) or in isolated tissue bioassays [pA(2) values of 8.5-9.6 for alpha(1A)-receptors in rat vas deferens or canine prostate strips, 8.9 at alpha(1D)-adrenoceptors (rat aorta), compared with 7.1 at alpha(1B)-adrenoceptors (rat spleen)]. Furthermore, the compound antagonized putative alpha(1L)-adrenoceptors in the rabbit urethra (pA(2) value of 7.58). Fiduxosin blocked epinephrine-induced increases in canine IUP (pseudo-pA(2) value of 8.12), eliciting only transient decreases in mean arterial blood pressure(MAP) in SHR. The area under the curve (AUC(0-60) min) for the hypotensive response was dose related with a log index value for fiduxosin of 5.23, indicating a selectivity of 770-fold comparing IUP to MAP effects. Preferential antagonism of alpha(1A)- and alpha(1D)- versus alpha(1B)-adrenoceptors in vitro, blockade of putative alpha(1L)-sites in vitro, and selective effects on lower urinary tract function versus blood pressure in vivo by fiduxosin suggest-the potential utility of this compound for the treatment of BPH.