ABSTRACT
By screening a library of metalloenzyme inhibitors, the N-formyl-hydroxylamine derivative BB-3497 was identified as a potent inhibitor of Escherichia coli peptide deformylase with antibacterial activity both in vitro and in vivo. The homochiral synthesis of BB-3497, involving a novel asymmetric Michael addition reaction is described.
Subject(s)
Amidohydrolases , Aminopeptidases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Hydroxamic Acids/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Molecular Conformation , Structure-Activity RelationshipABSTRACT
Novel sulfonamide matrix metalloproteinase inhibitors of general formula (9) were synthesised by a route involving a stereoselective conjugate addition reaction. Enzyme selectivity was found to be dependant on the nature of the sulfonamide substituents. Compounds (9f, 9q) are potent selective collagenase inhibitors with good oral bioavailability.
Subject(s)
Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemical synthesis , Sulfonamides/chemical synthesis , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Biological Availability , Hydrogen Bonding , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Molecular Structure , Protease Inhibitors/pharmacology , Rats , Sulfonamides/pharmacologyABSTRACT
Matrix metalloproteinase inhibitors of general formula (1) were synthesised by a route involving an Ireland-Claisen rearrangement which enables systematic modification of the substituent alpha to the hydroxamic acid. An analogue (12c) possessing an alpha-cyclopentyl group is a potent broad spectrum inhibitor that displays high and sustained blood levels following oral dosing in both the rat and marmoset ex-vivo bioassays. This compound and analogues are also potent inhibitors of TNF alpha release.
Subject(s)
Hydroxamic Acids/chemical synthesis , Metalloendopeptidases/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Administration, Oral , Animals , Biological Availability , Callithrix , Depression, Chemical , Hydroxamic Acids/pharmacokinetics , Hydroxamic Acids/pharmacology , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/pharmacology , Rats , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
The total synthesis of the novel hydroxylated HMG-CoA reductase inhibitor dihydroeptastatin (7) is described. The key C-3 hydroxyl group is introduced via a Baeyer-Villiger reaction on the methyl ketone 17 which is obtained in three high-yielding steps from the known tricyclic lactone 12. In an isolated enzyme assay dihydroeptastatin had a similar IC50 to mevinolin but in cellular assays using Hep G2 and HES 9 cell lines, dihydroeptastatin was much less potent. No selectivity between the two cell lines was observed.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Pravastatin/analogs & derivatives , Animals , Hydroxymethylglutaryl CoA Reductases/pharmacology , Pravastatin/chemical synthesis , Pravastatin/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
A series of pyrimido[1,2-a]indoles were synthesized and studied for their hypoglycemic activity following oral administration at a standard dose of 100 mg/kg to fed rats. The effect of 10-alkoxyalkyl, 10-alkyl, 10-aryl, and 3,3-dialkyl substitution on the activity of 10-hydroxypyrimido[1,2-a]indoles was investigated. Relative potencies of a number of the most active compounds were defined by three-point dose-response studies. The most potent compounds were those with either 3,3-dimethyl substituents, compounds 21, 22, and 38, or 3,3-spirocyclohexane substituents, compounds 39 and 49. 10-Aminopyrimido[1,2-a]indoles were in general less active than the 10-hydroxy analogues, and potency was further decreased by derivatizing the 10-amino group. The most potent 10-amino derivatives were 57 and 58.
