title: Preclinical pharmacology of fiduxosin, a novel alpha(1)-adrenoceptor antagonist with uroselective properties.
abstract: Benign prostatic hyperplasia (BPH), common in aging males, is often treated with alpha(1)-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-methoxy-1,2,3,3a,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.
authors.affiliation: Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-6125, USA. art.a.hancock@abbott.com
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Hancock
authors.forename: Steven A
authors.initials: SA
authors.lastname: Buckner
authors.forename: Michael E
authors.initials: ME
authors.lastname: Brune
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Esbenshade
authors.forename: Lynne M
authors.initials: LM
authors.lastname: Ireland
authors.forename: Sweta
authors.initials: S
authors.lastname: Katwala
authors.forename: Ivan
authors.initials: I
authors.lastname: Milicic
authors.forename: Michael D
authors.initials: MD
authors.lastname: Meyer
authors.forename: James F
authors.initials: JF
authors.lastname: Kerwin
authors.forename: Michael
authors.initials: M
authors.lastname: Williams
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011470:Prostatic Hyperplasia / Q000188:drug therapy; D011744:Pyrimidinones / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR; D014521:Urethra / Q000187:drug effects / Q000502:physiology; D014551:Urinary Tract / Q000187:drug effects*; D014563:Urodynamics / Q000187:drug effects; D014649:Vas Deferens / Q000187:drug effects
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D006575:Heterocyclic Compounds, 3-Ring; D011744:Pyrimidinones; C447622:fiduxosin