An analysis of 66 published clinical candidates from Journal of Medicinal Chemistry has been conducted to shed light on which lead generation strategies are most frequently employed in identifying drug candidates. The most frequent lead generation strategy (producing a drug candidate) was based on starting points derived from previously known compounds (43%) followed by random high throughput screening (29%). The remainder of approaches included focused screening, structure-based drug design (SBDD), fragment-based lead generation (FBLG), and DNA-encoded library screening (DEL). An analysis of physicochemical properties on the hit-to-clinical pairs shows an average increase in molecular weight (ΔMW = +85) but no change in lipophilicity (ΔclogP = -0.2), although exceptions are noted. The majority (>50%) of clinical candidates were found to be structurally very different from their starting point and were more complex. Finally, several reports of noncovalent scaffolds modified by a covalent warhead using SBDD approaches are discussed.

01 Oct 2016·Tetrahedron

Structure determination, synthesis, and biological evaluation of a metabolite of the selective α1D adrenoceptor antagonist TAK-259

Author: Sakauchi, Nobuki ; Kuno, Haruhiko ; Kameoka, Nagako ; Miyamoto, Maki ; Miwa, Katsuhiko ; Furukawa, Hideki ; Shirai, Junya ; Maezaki, Hironobu ; Hara, Miki ; Tada, Norio ; Sato, Ayumu ; Fujita, Hisashi

5-Chloro-1-(5-chloro-2-(methylsulfonyl)benzyl)-2-imino-1,2-dihydropyridine-3-carboxamide hydrochloride (TAK-259) is a novel, selective, and orally active α_1D adrenoceptor antagonist with anti-urinary frequency effect.A metabolite I of TAK-259 was identified from monkey urine samples.To elucidate the structure of I, extraction and purification of the metabolite from TAK-259-treated monkey urine was conducted.Structural anal. of the purified compounds using NMR indicated the compound to be I.An authentic sample of compound I was synthesized via regioselective alkylation of 4-methoxypyridin-2-amine.The biol. activity of metabolite I was also evaluated, and the compound found not to possess affinity toward any known α₁ adrenoceptor subtype.

14 Apr 2016·Journal of Medicinal ChemistryQ1 · MEDICINE

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 α_1D Adrenoceptor Antagonist with Antiurinary Frequency Effects: Reducing Human Ether-a-go-go-Related Gene (hERG) Liabilities

Q1 · MEDICINE

Article

Author: Kuno, Haruhiko ; Kohara, Yasuhisa ; Imai, Yumi ; Sakauchi, Nobuki ; Sato, Ayumu ; Saikawa, Reiko ; Suzaki, Tomohiko ; Nagabukuro, Hiroshi ; Fujita, Hisashi ; Yoshida, Masato ; Kamo, Izumi ; Imai, Shigemitsu ; Okabe, Yuichi

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.

100 Deals associated with TAK-259

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Indication	Highest Phase	Country/Location	Organization	Date
Urinary Bladder, Overactive	Phase 1	Japan	Takeda Pharmaceutical Co., Ltd.	-

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