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1.
J Med Chem ; 44(3): 350-61, 2001 Feb 01.
Article in English | MEDLINE | ID: mdl-11462976

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 Relationship
2.
Br J Pharmacol ; 132(2): 547-55, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11159705

ABSTRACT

1. The effect of two derivatives of salicylate, 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) and 2-acetoxy-4-trifluoromethylbenzoic acid (triflusal), on the expression of several proteins displaying pro-inflammatory activities the regulation of which is associated to the transcription factor NF-kappaB, was assayed in the human astrocytoma cell line 1321N1. 2. Tumour necrosis factor-alpha (TNF-alpha) activated NF-kappaB as judged from both the appearance of kappaB-binding activity in the nuclear extracts, the degradation of IkappaB proteins in the cell lysates, and the activation of IkappaB kinases using an immunocomplex kinase assay with glutathione S-transferase (GST)-IkappaB proteins as substrates. 3. HTB up to 3 mM did not inhibit the nuclear translocation of NK-kappaB/Rel proteins as judged from electrophoretic mobility-shift assays; however, HTB inhibited the degradation of IkappaBbeta without significantly affecting the degradation of both IkappaBalpha and IkappaBepsilon. 4. In keeping with their inhibitory effect on IkappaBbeta degradation in the cell lysates, both HTB and triflusal inhibited the phosphorylation of GST-IkappaBbeta elicited by TNF-alpha, without affecting the phosphorylation of GST-IkappaBalpha. 5. The effect of both HTB and triflusal on kappaB-dependent trans-activation was studied by assaying the expression of both cyclo-oxygenase-2 (COX-2) and vascular cell adhesion molecule-1 (VCAM-1). HTB and triflusal inhibited in a dose-dependent manner the expression of COX-2 and VCAM-1 mRNA and the induction of COX-2 protein at therapeutically relevant concentrations. 6. These findings show the complexity of the biochemical mechanisms underlying the activation of NF-kappaB in the different cell types and extend the anti-inflammatory effects of HTB and triflusal to neural cells.


Subject(s)
Astrocytoma/metabolism , Brain Neoplasms/metabolism , NF-kappa B/metabolism , Salicylates/pharmacology , Blotting, Western , Cyclooxygenase 2 , DNA, Complementary/biosynthesis , Electrophoresis , Humans , Indicators and Reagents , Isoenzymes/biosynthesis , Membrane Proteins , Neoplasm Proteins/biosynthesis , Neurons/drug effects , Neurons/metabolism , Prostaglandin-Endoperoxide Synthases/biosynthesis , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured , Vascular Cell Adhesion Molecule-1/biosynthesis
3.
J Med Chem ; 40(4): 547-58, 1997 Feb 14.
Article in English | MEDLINE | ID: mdl-9046346

ABSTRACT

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/pharmacology
4.
Eur J Pharmacol ; 318(2-3): 341-7, 1996 Dec 30.
Article in English | MEDLINE | ID: mdl-9016924

ABSTRACT

UR-7280 (3-tert-butyl-1-propyl-5-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-y l]methyl]-1H-pyrazole-4-carboxylic acid) is a new and potent angiotensin AT1-selective receptor antagonist. Binding studies in rat liver membranes showed that UR-7280 is an apparently competitive antagonist. However, in rabbit aorta this compound antagonized the angiotensin II-induced contractile response in an insurmountable way, causing a significant reduction of the maximal response. Additional binding studies evidenced that UR-7280 has a slowly reversible binding profile, consistent with its functional properties in rabbit aorta. The results obtained with a series of structural analogues of UR-7280 demonstrated a relationship between the size of the pyrazole 3-substituent and the surmountable or insurmountable mode of antagonism, indicating that this position may play a key role in the interaction between the antagonist and the angiotensin AT1 receptor.


Subject(s)
Angiotensin Receptor Antagonists , Pyrazoles/pharmacology , Tetrazoles/pharmacology , Angiotensin II/antagonists & inhibitors , Animals , In Vitro Techniques , Male , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Rabbits , Rats , Structure-Activity Relationship , Vasoconstriction/drug effects
5.
J Med Chem ; 39(11): 2197-206, 1996 May 24.
Article in English | MEDLINE | ID: mdl-8667363

ABSTRACT

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/chemistry
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