Molecular modeling, design, synthesis, and biological activity of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives as potassium-competitive acid blockers.
A series of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives were designed and synthesized based on our docking model as potassium-competitive acid blockers (P-CABs). Molecular modeling of these derivatives led us to introduce a substituent at the 1-position to access two lipophilic sites and polar residues. We identified potent P-CABs that exhibit excellent inhibitory activity in vitro and in vivo. These results indicate that the 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives are promising lead compounds as P-CABs.
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd.
Yasuyoshi
Y
Arikawa
Atsushi
A
Hasuoka
Keizo
K
Hirase
Nobuhiro
N
Inatomi
Fumihiko
F
Sato
Yasunobu
Y
Hori
Terufumi
T
Takagi
Naoki
N
Tarui
Makiko
M
Kawamoto
Masahiro
M
Kajino
D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005744:Gastric Acid / Q000378:metabolism; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D011188:Potassium; D054328:Proton Pump Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D054328:Proton Pump Inhibitors; D011725:Pyridines; D006632:Histamine; D017506:H(+)-K(+)-Exchanging ATPase; D011188:Potassium