ABSTRACT
A new class of MMP-12 inhibitors was discovered and optimized using structure-based drug design methods. Modeling studies using a known MMP-12 crystal structure identified a new interaction mode for these new MMP-12 inhibitors. Further optimization resulted in the discovery of a compound displaying nanomolar activity against MMP-12 and which was co-crystallized with MMP-12.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Metalloendopeptidases/antagonists & inhibitors , Binding Sites , Chelating Agents/chemistry , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/chemistry , Humans , Matrix Metalloproteinase 12 , Metalloendopeptidases/chemistry , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Zinc/chemistryABSTRACT
The synthesis and SAR studies of a series of structurally novel small molecule inhibitors of PDE7 are discussed. The best compounds from the series displayed low nanomolar inhibitory activity and are selective versus PDE4.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Isoenzymes/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Thiadiazoles/chemical synthesis , Thiadiazoles/pharmacology , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Cell Line , Cyclic Nucleotide Phosphodiesterases, Type 4 , Cyclic Nucleotide Phosphodiesterases, Type 7 , Humans , Isoenzymes/metabolism , Phosphodiesterase Inhibitors/chemistry , Structure-Activity Relationship , Thiadiazoles/chemistryABSTRACT
The synthesis and optimization of pharmacokinetic parameters of structurally novel small PDE7 inhibitors is discussed.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Isoenzymes/antagonists & inhibitors , Phosphodiesterase Inhibitors/pharmacokinetics , Thiadiazoles/pharmacokinetics , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Administration, Oral , Animals , Biological Availability , Cyclic Nucleotide Phosphodiesterases, Type 7 , Isoenzymes/metabolism , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/chemistry , Rats , Stereoisomerism , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistryABSTRACT
The synthesis and SAR studies of spiroquinazolinones as novel PDE7 inhibitors are discussed. The best compounds from the series displayed nanomolar inhibitory affinity and were selective versus other PDE isoenzymes.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Isoenzymes/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemical synthesis , Quinazolines/chemical synthesis , Spiro Compounds/chemical synthesis , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Cell Line , Cyclic Nucleotide Phosphodiesterases, Type 7 , Drug Evaluation, Preclinical , Humans , Isoenzymes/metabolism , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Solubility , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
The optimization of 5,8-disubstituted spirocyclohexane-quinazolinones into potent, selective, soluble PDE7 inhibitors with acceptable in vivo pharmacokinetic parameters is presented.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Isoenzymes/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacokinetics , Quinazolines/chemical synthesis , Spiro Compounds/chemical synthesis , 3',5'-Cyclic-AMP Phosphodiesterases/classification , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Animals , Biological Availability , Cell Line , Cyclic Nucleotide Phosphodiesterases, Type 7 , Half-Life , Humans , In Vitro Techniques , Isoenzymes/classification , Isoenzymes/metabolism , Microsomes/drug effects , Microsomes/metabolism , Quinazolines/chemistry , Quinazolines/pharmacology , Rats , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
Human macrophage elastase (MMP-12) plays an important role in inflammatory processes and has been implicated in diseases such as emphysema and chronic obstructive pulmonary disease (COPD). It is therefore an attractive target for therapeutic agents. As part of a structure-based drug design programme to find new inhibitors of MMP-12, the crystal structures of the MMP-12 catalytic domain (residues 106-268) complexed to three different non-peptidic small molecule inhibitors have been determined. The structures reveal that all three ligands bind in the S1' pocket but show varying degrees of interaction with the Zn atom. The structures of the complexes with inhibitors CP-271485 and PF-00356231 reveal that their central morpholinone and thiophene rings, respectively, sit over the Zn atom at a distance of approximately 5A, locating the inhibitors halfway down the S1' pocket. In both of these structures, an acetohydroxamate anion, an artefact of the crystallisation solution, chelates the zinc atom. By contrast, the acetohydroxamate anion is displaced by the ligand in the structure of MMP-12 complexed to PD-0359601 (Bayer), a potent zinc chelating N-substituted biaryl butyric acid, used as a reference compound for crystallisation. Although a racemate was used for the crystallisation, the S enantiomer only is bound in the crystal. Important hydrophobic interactions between the inhibitors and residues from the S1' pocket are observed in all of the structures. The relative selectivity displayed by these ligands for MMP-12 over other MMP family members is discussed.
