ABSTRACT
The synthesis and pharmacological activity of a series of bicyclic pyrazolo[1,5-a]pyrimidines as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema and air-pouch model). Modification of the pyrimidine substituents showed that 6,7-disubstitution provided the best activity and led to the identification of 3-(4-fluorophenyl)-6,7-dimethyl-2-(4-methylsulfonylphenyl)pyrazolo[1,5-a]pyrimidine (10f) as one of the most potent and selective COX-2 inhibitor in this series.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Isoenzymes/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Carrageenan , Cell Line , Cyclooxygenase 1 , Cyclooxygenase 2 , Edema/drug therapy , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Exudates and Transudates/enzymology , Humans , Male , Membrane Proteins , Prostaglandin-Endoperoxide Synthases , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Stomach/enzymology , Structure-Activity RelationshipABSTRACT
The synthesis and pharmacological activity of a new series of 5-(biphenyl-4-ylmethyl)pyrazoles as potent angiotensin II antagonists both in vitro (binding of [3H]AII) and in vivo (iv, inhibition of AII-induced increase in blood pressure, pithed rats; po, furosemide-treated sodium-depleted rats) are reported. The various substituents of the pyrazole ring have been modified taking into account the receptor's requirements derived from related structure-activity relationship studies. A propyl or butyl group at position 1 as well as a carboxylic acid group at position 4 were shown to be essential for high affinity. Different groups at position 3 (H, small alkyl, phenyl, benzyl) provided good binding affinity, but oral activity was highly discriminating: bulky alkyl groups provided the highest potencies. Among the acidic isosteres tested in the biphenyl moiety, the tetrazole group proved to be the best. Compound 14n (3-tert-butyl-1-propyl-5-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-y l] methyl]-1H-pyrazole-4-carboxylic acid, UR-7280) shows high potency both in vitro (IC50 = 3 nM) and in vivo (iv, 61.2 +/- 10% decrease in blood pressure at 0.3 mg/kg; po, 30 mmHg fall in blood pressure at 0.3 mg/kg), in comparison to losartan (IC50 = 59 nM; iv, 62.5 +/- 8.9% decrease in blood pressure at 1 mg/kg; po, 13 mmHg fall in blood pressure at 3 mg/kg). These data, together with the good pharmacokinetic profile of 14n in different species, have led to its selection for clinical evaluation as an antihypertensive agent.
Subject(s)
Angiotensin Receptor Antagonists , Antihypertensive Agents/chemical synthesis , Pyrazoles/chemistry , Tetrazoles/chemistry , Angiotensin I/metabolism , Animals , Antihypertensive Agents/chemistry , Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Rats , Structure-Activity Relationship , Tetrazoles/chemical synthesis , Tetrazoles/pharmacologyABSTRACT
The synthesis and pharmacological evaluation of a new series of potent AT1 selective diphenylpropionic acid nonpeptide angiotensin II receptor antagonists are reported. The new compounds were evaluated for in vitro AT1 (rat liver) and AT2 (rat adrenal) binding affinity as well as for in vivo inhibition of angiotensin II-induced increase in mean arterial blood pressure in pithed rats. Unsaturation of the diphenylpropionic acids as well as substitution or replacement by alkyl groups of the pendant phenyl ring resulted in a decrease of potency. On the other hand, the presence of small alkyl groups in the alpha-position to the carboxylic acid was important for activity, with one of the resultant diastereoisomers (R*,R*) being ca. 10-fold more active than the other (R*,S*). Oral evaluation of the most active compounds in a furosemide-treated sodium-depleted rat model showed that compound 36g (UR-7198) reduced blood pressure dose dependently. This compound showed in vitro and iv potencies similar to that of the reference compound losartan but faster onset of action and somewhat greater oral activity, presumably due to its improved bioavailability.
Subject(s)
Angiotensin II/antagonists & inhibitors , Angiotensin Receptor Antagonists , Antihypertensive Agents/chemistry , Antihypertensive Agents/chemical synthesis , Imidazoles/chemistry , Imidazoles/chemical synthesis , Phenylpropionates/chemistry , Phenylpropionates/chemical synthesis , Administration, Oral , Adrenal Glands/metabolism , Angiotensin II/pharmacology , Animals , Antihypertensive Agents/pharmacology , Aorta, Thoracic , Biphenyl Compounds/chemistry , Blood Pressure/drug effects , Diet, Sodium-Restricted , Furosemide/pharmacology , Imidazoles/pharmacology , In Vitro Techniques , Indicators and Reagents , Kinetics , Liver/metabolism , Losartan , Male , Models, Molecular , Molecular Structure , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Phenylpropionates/pharmacology , Rabbits , Rats , Stereoisomerism , Structure-Activity Relationship , Tetrazoles/chemistryABSTRACT
A new series of 2,2-dialkylnaphthalen-1-one potassium channel activators has been prepared, and their in vitro relaxant activities in isolated rat portal vein and guinea pig tracheal spirals as well as their oral antihypertensive effect in spontaneously hypertensive rats have been evaluated. The group of 1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethylnaphthalen -1- ones with an electron-withdrawing substituent at the 6-position contain the most active compounds and 1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-1-oxonaphtha lene-6- carbonitrile, 17f (UR-8225), has been selected for further pharmacological development.
