A prodrug approach towards the development of tricyclic-based FBPase inhibitors.
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.
Tsukada
Tomoharu
T
Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Tamaki
Kazuhiko
K
Tanaka
Jun
J
Takagi
Toshiyuki
T
Yoshida
Taishi
T
Okuno
Akira
A
Shiiki
Takeshi
T
Takahashi
Mizuki
M
Nishi
Takahide
T
D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000882:Haplorhini; D008968:Molecular Conformation; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D011355:Prodrugs; D011725:Pyridines; D013844:Thiazoles; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000409:Alanine