Synthesis and antihypertensive activity of 5-O-substituted derivatives of 5-hydroxypicolinic acid.
5-O-Substituted derivatives of 5-hydroxypicolinic acids were synthesized from nojirimycin and studied for their antihypertensive activity in unanesthetized spontaneously hypertensive rats (SHRs) restrained in wire mesh cage and acute toxicity in mice. 5-n-Butoxy-picolinic acid (ND-186) was found to have antihypertensive activity comparable to fusaric acid and lesser acute toxicity. Introduction of halogeno group, in particular trifluoromethyl group to the omega-position of 5-n-butoxy group resulted in the enhancement of antihypertensive activity. The acute toxicity was also lowered 3-5 times compared to that of fusaric acid. Replacement of alkyl group with phenyl group resulted in a slight increment of activity. Some of ester derivatives of ND-186 potentiated the antihypertensive activity and reduced the acute toxicity. There was good correlation between partition coefficient (log P) of ester groups and their antihypertensive activities; compound with higher lipophilicity showed higher antihypertensive activity under the condition of oral administration. However, esterification of other compounds such as 5-halogenoalkoxy- and 5-(substituted) phenoxypicolinic acid was not accompanied with activity increment. Considering from the balance of the antihypertensive activity in SHRs and the acute toxicity in mice, 5-(5',5',5'-trifluoropentoxy)-picolinic acid was selected as a candidate for further evaluation.
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis*; D001794:Blood Pressure / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D006339:Heart Rate / Q000187:drug effects; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D010848:Picolinic Acids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D010848:Picolinic Acids