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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 330; no. 3; pp. 892 - 901
• Main Authors: Conlon, Kelly, Christy, Clare, Westbrook, Simon, Whitlock, Gavin, Roberts, Lee, Stobie, Alan, McMurray, Gordon
• Format: Journal Article
• Language: English
• Published: United States 01.09.2009
• Subjects: Adrenergic alpha-1 Receptor Agonists; Adrenergic alpha-Agonists - pharmacology; Animals; Blood Pressure - drug effects; Cell Line; CHO Cells; Cricetinae; Cricetulus; DNA, Complementary - biosynthesis; DNA, Complementary - genetics; Dogs; Female; Heart Rate - drug effects; Hemodynamics - drug effects; Humans; Imidazoles - pharmacology; Radioligand Assay; Receptors, Adrenergic, alpha-1 - biosynthesis; Sulfonamides - pharmacology; Telemetry; Urethra - drug effects; Urethra - metabolism
• ISSN: 1521-0103
• DOI: 10.1124/jpet.109.154963

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.