Novel potassium-channel openers: preparation and pharmacological evaluation of racemic and optically active N-(6-amino-3-pyridyl)-N'-bicycloalkyl-N"-cyanoguanidine derivatives.
The previous paper reported on the synthesis and pharmacological evaluation of N-(6-amino-3-pyridyl)-N'-bicycloalkyl-N"-cyanoguanidine derivatives, from among which three compounds were selected as potent potassium-channel openers. In the present study, selected compounds were tested for antagonism of potassium-induced contraction of rat aorta, hypotensive activity in normotensive rats, and diuretic activity in spontaneously hypertensive rats. This led to further evaluation of compound (+/-)-10 and selection of (+)-N-(6-amino-3-pyridyl)-N'- [(1S,2R,4R)-bicyclo- [2.2.1]hept-2-yl]-N"-cyanoguanidine ((+)-10) (AL0670) for development as an antihypertensive agent. Although AL0670 is regarded as a pinacidil-type K(+)-channel opener, it showed different pharmacological and conformational profiles from pinacidil.
Research Division, Green Cross Corporation, Osaka, Japan.
M
M
Eda
T
T
Takemoto
S
S
Ono
T
T
Okada
K
K
Kosaka
M
M
Gohda
S
S
Matzno
N
N
Nakamura
C
C
Fukaya
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D004232:Diuretics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007022:Hypotension / Q000139:chemically induced; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013237:Stereoisomerism
C088267:AL 0670; D000959:Antihypertensive Agents; D001643:Bridged Bicyclo Compounds; D004232:Diuretics; D006146:Guanidines; D015221:Potassium Channels