Discovery of 5-Chloro-1-(5-chloro-2-(methylsulfonyl)benzy1)-2-imino-1,2-dihydropyridine-3-carboxamide (TAK-259) as a Novel, Selective, and Orally Active α1D Adrenoceptor Antagonist with Antiurinary Frequency Effects: Reducing Human Ether-a-go-go-Related Gene (hERG) Liabilities

A novel structural class of iminopyridine derivative 1 was identified as a potent and selective human am adrenoceptor (alpha(1D) adrenergic receptor; alpha(1D)-AR) antagonist against alpha(1A)- and alpha(1B)-AR through screening of an in-house compound library. From initial structure activity relationship studies, we found lead compound 9m with hERG K+ channel liability. To develop analogues with reduced hERG K+ channel inhibition, a combination of site-directed mutagenesis and docking studies was employed. Further optimization led to the discovery of (R)-9s and 9u, which showed antagonistic activity by a bladder strip test in rats with bladder outlet obstruction, as well as ameliorated cystitis-induced urinary frequency in rats. Ultimately, 9u was selected as a clinical candidate. This is the first study to show the utility of iminopyridine derivatives as selective alpha(1D)-AR antagonists and evaluate their effects in vivo.