ABSTRACT
In search of antiinflammatory drugs with a new mechanism of action, U0126 was found to functionally antagonize AP-1 transcriptional activity via noncompetitive inhibition of the dual specificity kinase MEK with an IC50 of 0.07 microM for MEK 1 and 0.06 microM for MEK 2. U0126 can undergo isomerization and cyclization reactions to form a variety of products, both chemically and in vivo, all of which exhibit less affinity for MEK and lower inhibition of AP-1 activity than parent, U0126.
Subject(s)
Butadienes/chemistry , Enzyme Inhibitors/chemistry , Nitriles/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Biotransformation , Butadienes/pharmacokinetics , Butadienes/pharmacology , Cyclization , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , NF-kappa B/antagonists & inhibitors , Nitriles/pharmacokinetics , Nitriles/pharmacology , Rats , Transcription Factor AP-1/antagonists & inhibitorsABSTRACT
Substituted pyrazoles, 1,2,4-triazoles, and tetrazoles are good surrogates for cis-amide bonds in a series of boronate ester thrombin inhibitors.
Subject(s)
Amides/pharmacology , Boronic Acids/pharmacology , Pyrazoles/pharmacology , Tetrazoles/pharmacology , Thrombin/antagonists & inhibitors , Thrombin/chemistry , Triazoles/pharmacology , Amides/chemistry , Binding Sites , Boronic Acids/chemistry , Crystallography, X-Ray , Indicators and Reagents , Models, Molecular , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Stereoisomerism , Structure-Activity Relationship , Tetrazoles/chemical synthesis , Tetrazoles/chemistry , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
AT1 and AT2 are the two major receptor subtypes for angiotensin II that have been pharmacologically defined by using the selective ligands losartan and PD123177, respectively. EXP597 (4-[(5-(2-benzoyl)benzyloxycarbonyl-4-ethyl-2-n-propylimidazole-1- yl)methyl]-3-fluoro-2'-isoamyloxycarbonylaminosulfonyl-[1,1']-biph enyl, potassium salt) is a nonpeptide angiotensin II receptor ligand which in the rat adrenal exhibits binding affinities (IC50) of 0.5 and 0.7 nM for angiotensin AT1 and AT2 receptor subtypes, respectively. Further, EXP597 is an insurmountable angiotensin II receptor antagonist in the isolated rabbit aorta and lowers blood pressure in renal hypertensive rats with i.v. and p.o. ED30 values of 0.05 and 0.9 mg/kg, respectively.
Subject(s)
Adrenal Cortex/metabolism , Adrenal Medulla/metabolism , Angiotensin Receptor Antagonists , Aorta/metabolism , Imidazoles/metabolism , Renin-Angiotensin System/drug effects , Sulfonamides/metabolism , Administration, Oral , Adrenal Cortex/drug effects , Adrenal Medulla/drug effects , Animals , Aorta/drug effects , Binding, Competitive , Biphenyl Compounds/metabolism , Biphenyl Compounds/pharmacology , Biphenyl Compounds/therapeutic use , Disease Models, Animal , Dose-Response Relationship, Drug , Hypertension, Renal/drug therapy , Imidazoles/administration & dosage , Imidazoles/pharmacology , Imidazoles/therapeutic use , In Vitro Techniques , Injections, Intravenous , Losartan , Male , Pyridines/metabolism , Pyridines/pharmacology , Pyridines/therapeutic use , Rabbits , Radioligand Assay , Rats , Rats, Inbred SHR , Rats, Sprague-Dawley , Receptors, Angiotensin/metabolism , Sulfonamides/administration & dosage , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Tetrazoles/metabolism , Tetrazoles/pharmacology , Tetrazoles/therapeutic useABSTRACT
A new series of nonpeptide angiotensin II (AII) receptor antagonists has been prepared. These N-(biphenylyl-methyl)imidazoles, e.g. 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5- (hydroxymethyl)imidazole, differ from the previously reported N-(benzamidobenzyl)imidazoles and related compounds in that they produce a potent antihypertensive effect upon oral administration; the earlier series generally were active only when administered intravenously. It has been found that the acidic group at the 2'-position of the biphenyl is essential. Only ortho-substituted acids possess both high affinity for the AII receptor and good oral antihypertensive potency. The carboxylic acid group has been replaced with a variety of acidic isosteres, and the tetrazole ring has been found to be the most effective. The tetrazole derivative, DuP 753, is currently in development for the treatment of hypertension.
