Metabolites of the angiotensin II antagonist tasosartan: the importance of a second acidic group.
Described in this paper is the synthesis and pharmacological activity of five metabolites of the angiotensin II antagonist tasosartan (1). Of particular interest is the effect of the additional acidic group of the enol metabolite (8) on activity. As suggested by the structural-activity relationship of other angiotensin II antagonist series, a second acidic group can improve receptor binding activity but decrease in vivo activity after oral dosing. The metabolic introduction of a second acidic group in tasosartan bypasses this problem and contributes to the excellent profile of the compound. A molecular modeling study provides a rationale for the role of the enol group of 8 in AT1 receptor binding.
Divisions of Chemical Sciences, Cardiovascular and Metabolic Disorders, and Structural Biology, Wyeth-Ayerst Research, CN 8000, Princeton, New Jersey 08543, USA.
J W
JW
Ellingboe
M D
MD
Collini
D
D
Quagliato
J
J
Chen
M
M
Antane
J
J
Schmid
D
D
Hartupee
V
V
White
C H
CH
Park
T
T
Tanikella
J F
JF
Bagli
D000284:Administration, Oral; D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000503:physiopathology; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D011728:Pyridones / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000378:metabolism*
C115423:2,4-dimethyl-5-hydroxy-8-(2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl)-8H-pyrido(2,3-d)pyrimidin-7-one; D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D011728:Pyridones; D011743:Pyrimidines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C086167:tasosartan