Cardioselective anti-ischemic ATP-sensitive potassium channel openers. 3. Structure-activity studies on benzopyranyl cyanoguanidines: modification of the cyanoguanidine portion.
Structure-activity relationships for the cyanoguanidine portion of the lead cardiac selective ATP-sensitive potassium channel (KATP) opener (3) are described. The cyanoguanidine moity appears to be optimal since increasing or decreasing the distance between the aniline nitrogen and the pendant aromatic ring attenuates anti-ischemic potency/selectivity. Similarly, unfavorable results are obtained by replacement of the aniline nitrogen with other linkers (CH2, S, O). Replacement of the phenyl ring with a methyl group diminishes cardiac selectivity. Constraining the urea moiety into a benzimidazolone or imidazolone ring retains anti-ischemic potency with significant improvement in cardiac selectivity. As shown by the ratio of vasorelaxant and anti-ischemic potencies, the cardiac selectivity in vitro varies over 3 orders of magnitude. These data are in agreement with previous results indicating that distinct structure-activity relationships exist for the anti-ischemic and vasorelaxant activities. Since the anti-ischemic effects of this series of compounds are abolished by pretreatment with structurally different KATP blockers (glyburide, sodium 5-hydroxydecanoate, meclofenamic acid), the mechanism for the anti-ischemic actions of these compounds still appears to involve the opening of KATP.
Atwal
K S
KS
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
Grover
G J
GJ
Ahmed
S Z
SZ
Sleph
P G
PG
Dzwonczyk
S
S
Baird
A J
AJ
Normandin
D E
DE
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D017202:Myocardial Ischemia / Q000188:drug therapy*; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
D006146:Guanidines; D015221:Potassium Channels; D014665:Vasodilator Agents; D000255:Adenosine Triphosphate; C004711:dicyandiamido