The discovery of potent glycine transporter type-2 inhibitors: design and synthesis of phenoxymethylbenzamide derivatives

Eiki Takahashi; Tadamasa Arai; Masato Akahira; Mayumi Nakajima; Kazumi Nishimura; Yu Omori; Hiroki Kumagai; Tomohiko Suzuki; Ryoji Hayashi

doi:10.1016/j.bmcl.2014.06.059

The discovery of potent glycine transporter type-2 inhibitors: design and synthesis of phenoxymethylbenzamide derivatives

Bioorg Med Chem Lett. 2014 Sep 15;24(18):4603-4606. doi: 10.1016/j.bmcl.2014.06.059. Epub 2014 Jun 27.

Authors

Eiki Takahashi¹, Tadamasa Arai², Masato Akahira³, Mayumi Nakajima⁴, Kazumi Nishimura⁵, Yu Omori⁶, Hiroki Kumagai⁷, Tomohiko Suzuki⁸, Ryoji Hayashi⁹

Affiliations

¹ Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: eiki_takahashi@nts.toray.co.jp.
² Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: tadamasa_arai@nts.toray.co.jp.
³ Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: masato_akahira@nts.toray.co.jp.
⁴ Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: mayumi_nakajima@nts.toray.co.jp.
⁵ Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: kazumi_nishimura@nts.toray.co.jp.
⁶ Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: yu_omori@nts.toray.co.jp.
⁷ Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: hiroki_kumaga@nts.toray.co.jp.
⁸ Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: tomohiko_suzuki@nts.toray.co.jp.
⁹ Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: ryoji_hayashi2@nts.toray.co.jp.

PMID: 25176190
DOI: 10.1016/j.bmcl.2014.06.059

Abstract

We describe the discovery of phenoxymethylbenzamide derivatives as a novel class of glycine transporter type-2 (GlyT-2) inhibitors. We found hit compound 1 (human GlyT-2, IC50=4040 nM) in our library and converted its 1-(1-(naphthalen-2-ylmethyl)piperidin-4-yl)pyrrolidin-3-yl group to an 1-(N,N-dimethylaminopropyl)piperidyl group and its tert-butyl group to a trifluoromethyl group to obtain N-(1-(3-(dimethylamino)propyl)piperidin-4-yl)-4-((4-(trifluoromethyl)phenoxy)methyl)benzamide (20). Compound 20 showed good inhibitory activity against human GlyT-2 (IC50=15.3 nM) and exhibited anti-allodynia effects in a mouse neuropathic pain model.

Keywords: Glycine transporter type-2 inhibitor; Neuropathic pain; Phenoxymethylbenzamide derivatives.

MeSH terms

Benzamides / chemical synthesis
Benzamides / chemistry
Benzamides / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors*
Humans
Molecular Structure
Structure-Activity Relationship

Substances

Benzamides
Glycine Plasma Membrane Transport Proteins
SLC6A5 protein, human