Discovery of potent α1L-adrenoceptor agonists: Design and synthesis of bicyclic derivatives

Shinya Suzuki; Tsubasa Okano; Rie Horiuchi; Nana Hareyama; Kazutoshi Amikura; Naoyoshi Yamamoto; Yoshitaka Yoshizawa; Mai Yagi; Kanako Serizawa; Ryoji Hayashi

doi:10.1016/j.bmcl.2015.05.049

Discovery of potent α1L-adrenoceptor agonists: Design and synthesis of bicyclic derivatives

Bioorg Med Chem Lett. 2015 Aug 15;25(16):3368-72. doi: 10.1016/j.bmcl.2015.05.049. Epub 2015 May 31.

Authors

Affiliations

¹ Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: Shinya_Suzuki@nts.toray.co.jp.
² Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: Tsubasa_Okano@nts.toray.co.jp.
³ Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: Rie_Horiuchi@nts.toray.co.jp.
⁴ Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: Nana_Hareyama@nts.toray.co.jp.
⁵ Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: Kazutoshi_Amikura@nts.toray.co.jp.
⁶ Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: Naoyoshi_Yamamoto@nts.toray.co.jp.
⁷ Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: Yoshitaka_Yoshizawa@nts.toray.co.jp.
⁸ Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: Mai_Yagi@nts.toray.co.jp.
⁹ Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: Kanako_Serizawa@nts.toray.co.jp.
¹⁰ Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: Ryoji_Hayashi2@nts.toray.co.jp.

PMID: 26087939
DOI: 10.1016/j.bmcl.2015.05.049

Abstract

We aimed to create a novel and potent α(1L)-adrenoceptor agonist because such agonists are possible drug candidates for stress urinary incontinence. We used ligand-based drug design and evaluated the α(1L)-adrenoceptor agonist activity of the designed compounds. Among them, tetrahydroquinoline derivative 50 showed the most potent activity (ratio of noradrenaline half maximal effective concentration, 0.0028) and effectively induced contraction of rat bladder neck.

Keywords: Adrenoceptor agonist; Drug discovery; Stress urinary incontinence.

MeSH terms

Adrenergic alpha-1 Receptor Agonists / chemical synthesis*
Adrenergic alpha-1 Receptor Agonists / chemistry
Adrenergic alpha-1 Receptor Agonists / pharmacology
Animals
Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
Bridged Bicyclo Compounds, Heterocyclic / chemistry
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Drug Discovery*
Molecular Structure
Quinolines / chemistry
Quinolines / pharmacology
Rats
Urinary Bladder / drug effects

Substances

Adrenergic alpha-1 Receptor Agonists
Bridged Bicyclo Compounds, Heterocyclic
Quinolines
1,2,3,4-tetrahydroquinoline