ABSTRACT
A series of 3-hydroxy-3-methylpipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was designed based on the observation of increased aggrecanase activity with substitution at the 3-position of the piperidine ring. Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group that binds in the S1' pocket. These compounds also possess markedly improved bioavailability and lower metabolic clearance compared to analogous 3,3-dimethyl-5-hydroxypipecolic hydroxamates. These improvements are attributed to lowered lipophilicity proximal to the metabolically labile hydroxamic acid. Synthesis, structure activity relationships, and in vivo efficacy data are described.
Subject(s)
Endopeptidases/drug effects , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacokinetics , Matrix Metalloproteinase Inhibitors , Pipecolic Acids/chemical synthesis , Pipecolic Acids/pharmacokinetics , Administration, Oral , Animals , Collagenases/metabolism , Drug Design , Endopeptidases/metabolism , Humans , Hydroxamic Acids/chemistry , Matrix Metalloproteinase 13 , Molecular Structure , Pipecolic Acids/chemistry , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Structure-Activity RelationshipABSTRACT
A series of pipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was discovered based on screening known inhibitors of TNF-alpha converting enzyme (TACE). Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group. Incorporation of geminal alkyl substitution at the 3-position of the piperidine ring improved metabolic stability, presumably by increasing steric hindrance around the metabolically labile hydroxamic acid. This modification also resulted in dramatic improvement of aggrecanase activity with a slight reduction in selectivity versus MMP-1. Synthesis, structure activity relationships, and strategies to reduce metabolic clearance are described.
Subject(s)
Endopeptidases/drug effects , Hydroxamic Acids/pharmacology , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/pharmacology , Hydroxamic Acids/chemistry , Matrix Metalloproteinase 13 , Protease Inhibitors/chemistryABSTRACT
N-Hydroxy-3-hydroxy-4-arylsulfonyltetrahydropyranyl-3-carboxamides were designed as novel inhibitors of MMP-13 and aggrecanase based on known endocyclic hydroxamate inhibitors of matrix metalloproteinases. These compounds offer favorable physicochemical properties and low metabolic clearance. Synthesis and structure-activity relationships are reported.
Subject(s)
Endopeptidases/metabolism , Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemical synthesis , Pyrans/chemical synthesis , Animals , Collagenases/chemistry , Endopeptidases/chemistry , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacokinetics , Matrix Metalloproteinase 1/chemistry , Matrix Metalloproteinase 13 , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Pyrans/chemistry , Pyrans/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
A series of novel MMP-13 and TNF-alpha converting enzyme inhibitors based on piperazine 2-hydroxamic acid scaffolds are described. The TACE, MMP-1 and MMP-13 activity of these inhibitors as well as the effect of substitution of the piperazine nitrogen and the P-1' benzyloxy tailpiece is discussed. Moderate in vivo activity is observed with several members of this group.
