8-(3-chloro-4-methoxybenzyl)-8H-pyrido[2,3-d]pyrimidin-7-one derivatives as potent and selective phosphodiesterase 5 inhibitors

Toshiaki Sakamoto; Yuichi Koga; Masataka Hikota; Kenji Matsuki; Hideki Mochida; Kohei Kikkawa; Kotomi Fujishige; Jun Kotera; Kenji Omori; Hiroshi Morimoto; Koichiro Yamada

doi:10.1016/j.bmcl.2015.02.041

8-(3-chloro-4-methoxybenzyl)-8H-pyrido[2,3-d]pyrimidin-7-one derivatives as potent and selective phosphodiesterase 5 inhibitors

Bioorg Med Chem Lett. 2015 Apr 1;25(7):1431-5. doi: 10.1016/j.bmcl.2015.02.041. Epub 2015 Feb 21.

Authors

Affiliations

¹ Medicinal Chemistry Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
² Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
³ Advanced Medical Research Laboratories, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
⁴ Advanced Medical Research Laboratories, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan; Industry and Academia Cooperation Research Project, Laboratory of Target and Drug Discovery, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
⁵ Medicinal Chemistry Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan. Electronic address: morimoto.hiroshi@md.mt-pharma.co.jp.

PMID: 25754491
DOI: 10.1016/j.bmcl.2015.02.041

Abstract

A novel series of highly selective phosphodiesterase 5 (PDE5) inhibitors was found. 8H-Pyrido[2,3-d]pyrimidin-7-one derivatives bearing an (S)-2-(hydroxymethyl)pyrrolidin-1-yl group at the 2-position and a 3-chloro-4-methoxybenzyl group at the 8-position exhibited potent PDE5 inhibitory activities and high PDE5 selectivity over PDE6. Among the synthesized compounds, the 5-methyl analogue (5b) showed the most potent relaxant effect on isolated rabbit corpus cavernosum with an EC30 value of 0.85 nM.

Keywords: Erectile dysfunction; PDE5; PDE6.

MeSH terms

Animals
Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism*
Dose-Response Relationship, Drug
Molecular Structure
Phosphodiesterase 5 Inhibitors / chemical synthesis
Phosphodiesterase 5 Inhibitors / chemistry
Phosphodiesterase 5 Inhibitors / pharmacology*
Pyridones / chemical synthesis
Pyridones / chemistry
Pyridones / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Rabbits
Structure-Activity Relationship

Substances

Phosphodiesterase 5 Inhibitors
Pyridones
Pyrimidines
Cyclic Nucleotide Phosphodiesterases, Type 5