title: Pharmacological properties of 2-((R-5-chloro-4-methoxymethylindan-1-yl)-1H-imidazole (PF-3774076), a novel and selective alpha1A-adrenergic partial agonist, in in vitro and in vivo models of urethral function.
abstract: 2-((R-5-chloro-4-methoxymethyl-indan-1-yl)-1H-imidazole (PF-3774076) is a central nervous system (CNS) penetrant, potent, selective, partial agonist at the human alpha1(A)-adrenoceptor, demonstrating efficacy and selectivity in a range of binding and functional assays. In vivo, PF-3774076 increases peak urethral pressure in anesthetized female dogs in a dose-dependent manner, inducing changes in both the proximal and distal portions of the urethra via a central mechanism of action. The profile of this compound suggests that a CNS penetrant partial agonist at the alpha1(A)-adrenoceptor may offer significant benefit in stress urinary incontinence (SUI). However, despite partial agonism at the alpha1(A)-adrenoceptor and selectivity over alpha1(B)- and alpha1(D)-adrenoceptors, PF-3774076 did not offer the necessary degree of separation over cardiovascular events when assessed in in vivo models of cardiovascular function. This may be due to activation of both peripheral and central alpha1(A)-adrenoceptors. These data indicate that although central, partial alpha1(A)-agonists may offer significant benefit in the treatment of SUI, it may not be possible to achieve the desired level of urethral selectivity over cardiovascular events with this class of agent.
authors.affiliation: Department of Genitourinary Biology, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent, CT13 9NJ. Kelly.Conlon@pfizer.com
authors.forename: Kelly
authors.initials: K
authors.lastname: Conlon
authors.forename: Clare
authors.initials: C
authors.lastname: Christy
authors.forename: Simon
authors.initials: S
authors.lastname: Westbrook
authors.forename: Gavin
authors.initials: G
authors.lastname: Whitlock
authors.forename: Lee
authors.initials: L
authors.lastname: Roberts
authors.forename: Alan
authors.initials: A
authors.lastname: Stobie
authors.forename: Gordon
authors.initials: G
authors.lastname: McMurray
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D011869:Radioligand Assay; D018340:Receptors, Adrenergic, alpha-1 / Q000096:biosynthesis; D013449:Sulfonamides / Q000494:pharmacology; D013686:Telemetry; D014521:Urethra / Q000187:drug effects* / Q000378:metabolism
chemical_list: C543530:2-((R-5-chloro-4-methoxymethylindan-1-yl)-1H-imidazole); C547713:ADRA1A protein, human; D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D018076:DNA, Complementary; D007093:Imidazoles; D018340:Receptors, Adrenergic, alpha-1; D013449:Sulfonamides; C481520:dabuzalgron