Synthesis and pharmacological evaluation of N-(6-functionalized-amino-3-pyridyl)-N'-bicycloalkyl-N''-cyanoguanidine s as antihypertensive agents.
A series of amino acid conjugates of N-(6-amino-3-pyridyl)-N'-[exo-bicyclo[2.2.1]hept-2-yl]-N''- cyanoguanidine (4) were prepared and evaluated as antihypertensive agents. The parent compound 4 showed potent potassium channel-opening and antihypertensive activities, but with undesirable changes of the urinary balance of electrolytes. However, alanine and histidine congeners (9,19) reduced this undesirable side effect of 4 through improved pharmacokinetics without loss of antihypertensive activity. They also provided additional information on the structural requirements for pinacidil-type potassium channel openers.
Eda
M
M
Research Division, Green Cross Corporation, Osaka, Japan.
Takemoto
T
T
Okada
T
T
Sakashita
H
H
Matzno
S
S
Gohda
M
M
Hayashi
K
K
Nakamura
N
N
Fukaya
C
C
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D003864:Depression, Chemical; D004232:Diuretics / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D020110:Pinacidil; D011169:Portal Vein / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D004232:Diuretics; D006146:Guanidines; D015221:Potassium Channels; D020110:Pinacidil