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Vol. 300, Issue 2, 478-486, February 2002

Preclinical Pharmacology of Fiduxosin, a Novel alpha 1-Adrenoceptor Antagonist with Uroselective Properties

Arthur A. Hancock, Steven A. Buckner, Michael E. Brune, Timothy A. Esbenshade, Lynne M. Ireland, Sweta Katwala, Ivan Milicic, Michael D. Meyer, James F. Kerwin, Jr. and Michael Williams

Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois

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 [pA2 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 (pA2 value of 7.58). Fiduxosin blocked epinephrine-induced increases in canine IUP (pseudo-pA2 value of 8.12), eliciting only transient decreases in mean arterial blood pressure (MAP) in SHR. The area under the curve (AUC0right-arrow 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.

0022-3565/02/3002-0478$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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M. E. Brune, S. P. Katwala, I. Milicic, D. G. Witte, J. F. Kerwin Jr., M. D. Meyer, A. A. Hancock, and M. Williams
Effect of Fiduxosin, an Antagonist Selective for alpha 1A- and alpha 1D-Adrenoceptors, on Intraurethral and Arterial Pressure Responses in Conscious Dogs
J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 487 - 494.
[Abstract] [Full Text] [PDF]

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 J. Pharmacol. Exp. Ther.Home page
D. G. Witte, M. E. Brune, S. P. Katwala, I. Milicic, D. Stolarik, Y.-H. Hui, K. C. Marsh, J. F. Kerwin Jr., M. D. Meyer, and A. A. Hancock
Modeling of Relationships between Pharmacokinetics and Blockade of Agonist-Induced Elevation of Intraurethral Pressure and Mean Arterial Pressure in Conscious Dogs Treated with alpha 1-Adrenoceptor Antagonists
J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 495 - 504.
[Abstract] [Full Text] [PDF]


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