Nobuki Sakauchi

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

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.

Design, synthesis and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitor.

Centrally acting noradrenaline reuptake inhibitor (NRI) is reportedly effective for patients with stress urinary incontinence (SUI) by increasing urethral closure in the clinical Phase IIa study with esreboxetine. Noradrenaline transporters are expressed in both central and peripheral nervous systems and the contribution of each site to efficacy has not been clarified. This report describes the development of a series of peripheral-selective 7-phenyl-1,4-oxazepane NRIs to investigate the contribution of the peripheral site to increasing urethral resistance in rats. (6S,7R)-1,4-Oxazepane derivative 7 exhibited noradrenaline transporter inhibition with high selectivity against inhibitions of serotonin and dopamine transporters. A replacement of hydroxyl with acetamide group contributed to enhancement of peripheral selectivity by increasing molecular polarity. Compound 12, N-{[(6S,7R)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methyl}acetamide 0.5 fumarate, which showed effectively no brain penetration in rats, increased urethral resistance in a dose-dependent manner and exhibited a maximal effect on par with esreboxetine. These results demonstrate that the urethral resistance-increasing effects of NRI in rats are mainly caused by the inhibition of noradrenaline transporters in the peripheral sites.

Identification of a novel series of potent and selective CCR6 inhibitors as biological probes

CCR6 has been implicated in both autoimmune diseases and non-autoimmune diseases. Thus, inhibition of CCR6-dependent cell migration is an attractive strategy for their treatment. An orally available small molecule inhibitor of CCR6 could therefore be a useful biological probe for the pathophysiological studies. Initial SAR study of a hit compound provided potent N-benzenesulfonylpiperidine derivatives that suppressed CCL20-induced Gi signals. By subsequent scaffold morphing of the central ring and further optimization, we identified a novel series of 1,4-trans-1-benzenesulfonyl-4-aminocyclohexanes as potent and selective CCR6 inhibitors with good pharmacokinetic properties. Our compounds showed good correlation between Gi signal inhibitory activity and cell migration inhibitory activity in human CCR6-transfected CHO cells. In addition, representative compound 35 potently inhibited CCR6-dependent cell migration and the increase in ERK phosphorylation in human primary cells. Therefore, the compound could be used effectively as a biological probe against human CCR6.

Identification of 3,4-dihydro-2H-thiochromene 1,1-dioxide derivatives with a phenoxyethylamine group as highly potent and selective α1D adrenoceptor antagonists

A series of phenoxyethylamine derivatives was designed and synthesized to discover potent and selective human α1D adrenoceptor (α1D adrenergic receptor; α1D-AR) antagonists. Compound 7 was taken from our internal compound collection as an attractive starting point and exhibited moderate binding affinity for α1D-AR and high selectivity against α1A- and α1B-ARs. We focused on modifying the 2-methylsulfonylbenzyl group of 7 to discover novel compounds structurally distinct from other reported α1-AR antagonists containing the phenoxyethylamine motif. Study of structure activity relationship guided by a targeted ligand-lipophilicity efficiency score led to the discovery of a novel scaffold of 3,4-dihydro-2H-thiochromene 1,1-dioxide for selective α1D-AR antagonists. Further optimization studies resulted in the identification of (4S)-N4-[2-(2,5-difluorophenoxy)ethyl]-N6-methyl-3,4-dihydro-2H-thiochromene-4,6-diamine 1,1-dioxide, (S)-41, as a novel, highly potent and selective α1D-AR antagonist. Herein, we provide details of the structure activity relationship of the phenoxyethylamine analog for the potency and selectivity.