Subject(s)
Estradiol Congeners/chemical synthesis , Indoles/chemical synthesis , Animals , Bone Density/drug effects , Cell Line , Estradiol Congeners/chemistry , Estradiol Congeners/metabolism , Estradiol Congeners/pharmacology , Female , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Models, Molecular , Organ Size , Ovariectomy , Radioligand Assay , Rats , Structure-Activity Relationship , Transfection , Uterus/drug effectsABSTRACT
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.
Subject(s)
Angiotensin II/antagonists & inhibitors , Models, Molecular , Pyridones/chemical synthesis , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Tetrazoles/metabolism , Administration, Oral , Adrenal Glands/drug effects , Adrenal Glands/metabolism , Angiotensin II/metabolism , Angiotensin II Type 1 Receptor Blockers , Angiotensin II Type 2 Receptor Blockers , Angiotensin Receptor Antagonists , Animals , Blood Pressure/drug effects , Heart Rate/drug effects , Hypertension/physiopathology , In Vitro Techniques , Injections, Intravenous , Liver/drug effects , Liver/metabolism , Molecular Conformation , Pyridones/administration & dosage , Pyridones/chemistry , Pyridones/pharmacology , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Angiotensin, Type 1 , Receptor, Angiotensin, Type 2 , Receptors, Angiotensin/metabolism , Structure-Activity RelationshipABSTRACT
A series of pyrido[2,3-d]pyrimidine angiotensin II (A II) antagonists was synthesized and tested for antagonism of A II. Compounds with a biphenylyltetrazole pharmacophore and small alkyl groups at the 2- and 4-positions of the pyridopyrimidine ring were found to be the most potent in an AT1 receptor binding assay and in blocking the A II pressor response in anesthetized, ganglion-blocked A II-infused rats. 5,8-Dihydro-2,4-dimethyl-8-[(2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl)methyl]pyrido[2,3-d]pyrimidin-7(6H)-one (4a) was one of the more potent compounds in the binding assay and was the most efficacious compound in the A II-infused rat model. Further study of 4a in Goldblatt (2K-1C) rats showed the compound to have oral bioavailability and to be an efficacious and potent compound in a high renin form of hypertension.
