Novel, non-acylguanidine-type Na(+)/H(+) exchanger inhibitors: synthesis and pharmacology of 5-tetrahydroquinolinylidene aminoguanidine derivatives.
In the course of our research into new types of non-acylguanidine Na(+)/H(+) exchanger (NHE) inhibitors, we designed and synthesized aryl-fused tetrahydropyranylidene and cyclohexylidene aminoguanidine derivatives I (X = O, CH(2)), which were tested for their inhibitory effects on rat platelet NHEs. After optimization, we found that the S isomer of tetrahydroquinoline derivatives that possess a methyl group in the 4-position and a halogen or methyl group in the o-position of Ar(2) exhibited high inhibitory activity. In these compounds, (5E,7S)-[[7-(5-fluoro-2-methylphenyl)-4-methyl-7,8-dihydro-5(6H)-quinolinylidene]amino]guanidine dimethanesulfonate (18, T-162559) was found to be a potent inhibitor of both rat and human platelet NHEs, with IC(50) values of 14 and 13 nM, respectively. Furthermore, in a rat myocardial infarction model in vivo (1 h ischemia-24 h reperfusion), 18 (0.1 mg/kg, intravenously administered 5 min or 2 h before coronary occlusion) showed significant activity (33% or 23% inhibition, respectively). These results suggested that 18 may exhibit a potent and long-lasting protective activity against cardiac injuries induced by ischemia-reperfusion.
Fukumoto
Shoji
S
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Fukumoto_Shoji@takeda.co.jp
Imamiya
Eiko
E
Kusumoto
Keiji
K
Fujiwara
Shuji
S
Watanabe
Toshifumi
T
Shiraishi
Mitsuru
M
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002317:Cardiovascular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009203:Myocardial Infarction / Q000473:pathology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C433465:(7-(5-fluoro-2-methylphenyl)-4-methyl-7,8-dihydro-5(6H)-quinolinylideneamino)guanidine; D002317:Cardiovascular Agents; D006146:Guanidines; D011804:Quinolines; D017923:Sodium-Hydrogen Exchangers