ABSTRACT
A set of biphenyl aminoacid building blocks has been synthesized. These were used to construct partially-peptidic combinatorial libraries as equimolar multi-component samples. Activity of members of this library as vitronectin receptor antagonists is described, together with SAR studies of the most active members. These studies illustrate several important features of combinatorial libraries.
Subject(s)
Biphenyl Compounds/chemical synthesis , Databases as Topic , Receptors, Vitronectin/metabolism , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacokinetics , Biphenyl Compounds/pharmacology , Drug Design , Isomerism , Kinetics , Molecular Conformation , Molecular Structure , Receptors, Vitronectin/drug effects , Structure-Activity RelationshipABSTRACT
Tetracyclic guanines have been shown to be potent and selective inhibitors of the cGMP-hydrolyzing enzymes PDE1 and PDE5. In general, these compounds are inactive or only weakly active as inhibitors of PDE3, which is a major isozyme involved in cAMP hydrolysis. Structure-activity relationships are developed at N-1, C-2, N-3, and N-5 on the core nucleus. Compound 31, with an IC50 of 70 pM, is the most potent inhibitor of PDE1, while 50, with an IC50 of 4 nM, is the most potent inhibitor of PDE5. Compounds 20, 22, 30, and 50 are potent dual inhibitors with IC50 values below 30 nM for both PDE1 and PDE5. Compounds 12, 20, and 28 reduced blood pressure by more than 45 mmHg when administered orally at 10 mg/kg to the spontaneously hypertensive rat (SHR).
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , 3',5'-Cyclic-GMP Phosphodiesterases/antagonists & inhibitors , Antihypertensive Agents/chemical synthesis , Blood Pressure/drug effects , Guanine/analogs & derivatives , Guanine/chemical synthesis , Phosphodiesterase Inhibitors/chemical synthesis , Phosphoric Diester Hydrolases , Pyrroles , Administration, Oral , Animals , Antihypertensive Agents/chemistry , Antihypertensive Agents/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 1 , Cyclic Nucleotide Phosphodiesterases, Type 5 , Guanine/chemistry , Guanine/pharmacology , Indicators and Reagents , Isoenzymes/antagonists & inhibitors , Kinetics , Magnetic Resonance Spectroscopy , Molecular Structure , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , Rats , Rats, Inbred SHR , Structure-Activity RelationshipABSTRACT
A novel series of antiinflammatory agents, N-isoxazolyl-3-carboxamides of 4-hydroxy-2H-1,2-benzothiazine 1,1-dioxide, was synthesized and evaluated as antiinflammatory agents in the carrageenin-induced rat paw edema (CIRPE) assay and adjuvant-induced polyarthritis (AIP) assay. Several analogues were found to be equipotent or more potent than aspirin and phenylbutazone. Structure-activity relationships are discussed. One of the compounds, 4-hydroxy-2-methyl-N-(5-methyl-3-isoxazolyl)-2H-1,2-benzothiazine 3-carboxamide 1,1-dioxide (3a; isoxicam), was found to be 3 times as potent as phenylbutazone in the CIRPE and in the therapeutic AIP assays. Isoxicam (3a) is presently undergoing phase III clinical trial as an antiarthritic drug.
