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.
MeSH terms
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Administration, Oral
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Adrenergic alpha-1 Receptor Antagonists / administration & dosage
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Adrenergic alpha-1 Receptor Antagonists / chemistry*
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Adrenergic alpha-1 Receptor Antagonists / pharmacokinetics
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Adrenergic alpha-1 Receptor Antagonists / pharmacology*
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Animals
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Chemistry Techniques, Synthetic
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Cystitis / chemically induced
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Cystitis / drug therapy
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Disease Models, Animal
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Drug Discovery
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Drug Evaluation, Preclinical / methods
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
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Ether-A-Go-Go Potassium Channels / genetics
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Ether-A-Go-Go Potassium Channels / metabolism
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Humans
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Imines / administration & dosage
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Imines / chemistry*
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Imines / pharmacology*
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Molecular Docking Simulation
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Mutagenesis, Site-Directed
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Niacinamide / administration & dosage
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Niacinamide / analogs & derivatives*
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Niacinamide / chemistry
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Niacinamide / pharmacology
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Rats
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Receptors, Adrenergic, alpha-1 / metabolism*
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Structure-Activity Relationship
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Urinary Bladder / drug effects
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Urinary Bladder / physiology
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Urinary Bladder Neck Obstruction / drug therapy
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Urinary Bladder Neck Obstruction / physiopathology
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Urinary Bladder, Overactive / drug therapy
Substances
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ADRA1D protein, human
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Adrenergic alpha-1 Receptor Antagonists
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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Imines
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KCNH2 protein, human
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Receptors, Adrenergic, alpha-1
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TAK-259
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Niacinamide