Novel human metabolites of the angiotensin-II antagonist tasosartan and their pharmacological effects.
Three novel metabolites of the angiotensin-II (A-II) receptor antagonist tasosartan have been identified in humans, and the syntheses and pharmacologic profiling of these metabolites are reported. Each metabolite bound the human A-II receptor with IC(50)s between 20 and 45nM. The in vivo effects of these compounds in attenuating the pressor response to angiotensin-II challenge in anesthetized rats were also investigated. An unsaturated diol metabolite exhibited in vivo efficacy at intravenous doses of 1 and 3mg/kg, while the other metabolites, both carboxylic acids, had no significant effect at the same doses.
Medicinal Chemistry, Chemical Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, USA. elokdah@wyeth.com
Hassan M
HM
Elokdah
Gregory S
GS
Friedrichs
Sie Yearl
SY
Chai
Boyd L
BL
Harrison
John
J
Primeau
Michael
M
Chlenov
David L
DL
Crandall
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007275:Injections, Intravenous; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D011945:Receptors, Angiotensin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D011743:Pyrimidines; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C086167:tasosartan