A prodrug approach towards the development of tricyclic-based FBPase inhibitors

Tomoharu Tsukada; Kazuhiko Tamaki; Jun Tanaka; Toshiyuki Takagi; Taishi Yoshida; Akira Okuno; Takeshi Shiiki; Mizuki Takahashi; Takahide Nishi

doi:10.1016/j.bmcl.2010.03.017

A prodrug approach towards the development of tricyclic-based FBPase inhibitors

Bioorg Med Chem Lett. 2010 May 1;20(9):2938-41. doi: 10.1016/j.bmcl.2010.03.017. Epub 2010 Mar 7.

Authors

Tomoharu Tsukada¹, Kazuhiko Tamaki, Jun Tanaka, Toshiyuki Takagi, Taishi Yoshida, Akira Okuno, Takeshi Shiiki, Mizuki Takahashi, Takahide Nishi

Affiliation

¹ Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

PMID: 20359891
DOI: 10.1016/j.bmcl.2010.03.017

Abstract

For the purpose of reducing the strong CYP3A4 inhibitory potency of diamide prodrug 4, cyclic prodrugs of tricyclic-based FBPase inhibitors were synthesized. Extensive SAR studies led to the discovery of pyridine-containing cyclic prodrug 20, which strongly inhibited glucose production in monkey hepatocytes and also showed weak CYP3A4 inhibitory potency.

MeSH terms

Alanine / analogs & derivatives*
Alanine / chemical synthesis
Alanine / chemistry
Alanine / pharmacology
Animals
Cells, Cultured
Crystallography, X-Ray
Cytochrome P-450 CYP3A / metabolism
Cytochrome P-450 CYP3A Inhibitors*
Drug Design
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Haplorhini
Molecular Conformation
Organophosphonates / chemical synthesis
Organophosphonates / chemistry*
Organophosphonates / pharmacology
Prodrugs / chemical synthesis
Prodrugs / chemistry*
Prodrugs / pharmacology
Pyridines / chemistry*
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry*
Thiazoles / pharmacology

Substances

Cytochrome P-450 CYP3A Inhibitors
Enzyme Inhibitors
Organophosphonates
Prodrugs
Pyridines
Thiazoles
Cytochrome P-450 CYP3A
CYP3A4 protein, human
Alanine