Preclinical Pharmacology of Fiduxosin, a Novel α1-Adrenoceptor Antagonist with Uroselective Properties

  1. Arthur A. Hancock,
  2. Steven A. Buckner,
  3. Michael E. Brune,
  4. Timothy A. Esbenshade,
  5. Lynne M. Ireland,
  6. Sweta Katwala,
  7. Ivan Milicic,
  8. Michael D. Meyer,
  9. James F. Kerwin, Jr. and
  10. Michael Williams
  1. Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois
  1. Dr. Arthur A. Hancock, Department 4MN, AP9A/3, Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064-6125. E-mail:art.a.hancock{at}abbott.com

Abstract

Benign prostatic hyperplasia (BPH), common in aging males, is often treated with α1-adrenoceptor antagonists. To minimize hypotensive and other side effects, compounds with selective antagonist activity at α1A- and α1D- (compared with α1B-) adrenoceptors were evaluated that would block lower urinary tract α1-adrenoceptors in preference to cardiovascular α1B-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 α1a- (0.16 nM) and α1d-adrenoceptors (0.92 nM) in radioligand binding studies compared with α1b-adrenoceptors (25 nM) or in isolated tissue bioassays [pA2 values of 8.5–9.6 for α1A-receptors in rat vas deferens or canine prostate strips, 8.9 at α1D-adrenoceptors (rat aorta), compared with 7.1 at α1B-adrenoceptors (rat spleen)]. Furthermore, the compound antagonized putative α1L-adrenoceptors in the rabbit urethra (pA2value 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 (AUC0→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 α1A- and α1D- versus α1B-adrenoceptors in vitro, blockade of putative α1L-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.

Footnotes

  • ↵1 In this article, nomenclature used to differentiate among the subtypes of α1-adrenoceptors uses uppercase subscripted letters to describe tissue-sourced receptors and lowercase subscripts to define cloned receptors (Bylund et al., 1994).

  • Portions of these data were presented at the American Urological Association 2000 Meeting [Hancock A, Meyer M, Brune M, Buckner S, Esbenshade T, Drizin I, Sullivan J, Williams M, and Kerwin J (2000) Fidoxosin: An α1a/d receptor antagonist with enhanced in vivo urolselectivity relative to terazosin and tamsulosin. J Urol 163 (Suppl 4):310].

  • Abbreviations:
    BPH
    benign prostatic hyperplasia
    REC 15/2739
    (N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxamide)
    Ro-70-0004
    3-(3-{4-[fluoro-2-(2,2,2-trifluoroethoxy)-phenyl]-piperazin-1-yl}-propyl)-5-methyl-1H-pyrimidine-2,4-dione mono hydrochloride monohydrate
    fiduxosin (ABT-980)
    (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 hydrochloride)
    DMSO
    dimethyl sulfoxide
    PE
    phenylephrine
    IUP
    intraurethral pressure
    EPI
    epinephrine
    SHR
    spontaneously hypertensive rats
    MAP
    mean arterial blood pressure
    AUC
    area under the curve
    pED50
    negative logarithm of the molar dose of compound required to elicit a reduction in blood pressure for 60 min to a point midway between hypertensive and normotensive
    ANOVA
    analysis of variance
    Ki
    inhibition constant as a measure of drug affinity for a receptor, equivalent to the concentration of compound required to occupy 50% of receptors
    pKB
    negative logarithm of the dissociation constant
    pA2
    negative logarithm of the concentration of compound required to elicit a 2-fold shift of an agonist concentration-response curve in isolated tissues
    A-131701
    (3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b, hexahydro-[1H]-benz[e]isoindol-2-yl)ethyl]pyrido[3′,4′:4,5]thieno [3,2-d]pyrimidine-2,4(1H,3H)-dione)
    CL
    confidence limit
    B8805-033
    [(±)-1,3,5-trimethyl-6-[[3-[4-((2,3dihydro-2-hydroxymethyl)-1,4-benzodioxin-5-yl)-1-piperazinyl]pro-pyl]amino]-2,4(1H,3H)-pyrimidin-one]
    WB-4101
    [2-(2,5-dimethyoxyphenoxyethyl)-aminomethyl-1,4 benzodioxane
    BMY-7378
    (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-1-7,9-dione)
    RWJ-38063
    [N-(2-{4-[2-(methylethoxy)phenyl]piperazinyl}ethyl-2-(2-oxopiperadinyl)acetamide]
    RWJ-69736
    [N-(3-{4-[2-(methylethoxy)phenyl]piperazinyl}propyl-2-(2-oxopiperadinyl)acetamide]
    • Received July 24, 2001.
    • Accepted October 19, 2001.
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  1. doi: 10.1124/jpet.300.2.478 JPET February 1, 2002 vol. 300 no. 2 478-486
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