title: Discovery of 5-Chloro-1-(5-chloro-2-(methylsulfonyl)benzyl)-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.
abstract: A novel structural class of iminopyridine derivative 1 was identified as a potent and selective human α1D adrenoceptor (α1D adrenergic receptor; α1D-AR) antagonist against α1A- and α1B-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 α1D-AR antagonists and evaluate their effects in vivo.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Nobuki
authors.initials: N
authors.lastname: Sakauchi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Kohara
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Sato
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Suzaki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Imai
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Okabe
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Shigemitsu
authors.initials: S
authors.lastname: Imai
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Saikawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagabukuro
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Kuno
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Fujita
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Kamo
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000284:Administration, Oral; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D060326:Chemistry Techniques, Synthetic; D003556:Cystitis / Q000139:chemically induced / Q000188:drug therapy; D004195:Disease Models, Animal; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007097:Imines / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D016297:Mutagenesis, Site-Directed; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology; D001748:Urinary Bladder Neck Obstruction / Q000188:drug therapy / Q000503:physiopathology; D053201:Urinary Bladder, Overactive / Q000188:drug therapy
chemical_list: C547719:ADRA1D protein, human; D058668:Adrenergic alpha-1 Receptor Antagonists; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007097:Imines; C000606913:KCNH2 protein, human; D018340:Receptors, Adrenergic, alpha-1; C000610598:TAK-259; D009536:Niacinamide