ABSTRACT
A lead generation and optimization program delivered the highly selective and potent CatC inhibitor 10 as an in vivo tool compound and potential development candidate. Structural studies were undertaken to generate SAR understanding.
Subject(s)
Cathepsin C/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Humans , Indicators and Reagents , Models, Molecular , Molecular Conformation , Recombinant Proteins/chemistry , Spectrometry, Fluorescence , Structure-Activity Relationship , Substrate Specificity , X-Ray DiffractionABSTRACT
The optimization of a new series of muscarinic M(3) antagonists is described, leading to the identification of AZD9164 which was progressed into the clinic for evaluation of its potential as a treatment for COPD.
Subject(s)
Muscarinic Antagonists/chemistry , Piperidines/chemistry , Quinuclidines/chemistry , Receptor, Muscarinic M3/agonists , Blood Proteins/metabolism , Drug Evaluation, Preclinical , Humans , Muscarinic Antagonists/pharmacology , Muscarinic Antagonists/therapeutic use , Piperidines/pharmacology , Piperidines/therapeutic use , Protein Binding , Pulmonary Disease, Chronic Obstructive/drug therapy , Quinuclidines/pharmacology , Quinuclidines/therapeutic use , Receptor, Muscarinic M3/metabolism , Structure-Activity RelationshipABSTRACT
A novel series of biaryl phenoxyacetic acids was discovered as potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). A hit compound 4 was discovered from high throughput screening. Modulation of multiple aryl substituents afforded both agonists and antagonists, with small changes often reversing the mode of action. Understanding the complex SAR allowed design of potent antagonists such as potential candidate 34.
Subject(s)
Acetates/chemical synthesis , Receptors, Immunologic/agonists , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/agonists , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemistry , Acetates/pharmacology , Animals , Humans , Inhibitory Concentration 50 , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
By careful analysis of experimental X-ray ligand crystallographic protein data across several inhibitor series we have discovered a novel, potent and selective series of iNOS inhibitors exemplified by compound 8.
Subject(s)
Enzyme Inhibitors/chemistry , Isoxazoles/chemistry , Nitric Oxide Synthase Type II/antagonists & inhibitors , Pyridines/chemistry , Animals , Binding Sites , Computer Simulation , Crystallography, X-Ray , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , Mice , Microsomes, Liver/metabolism , Nitric Oxide Synthase Type II/metabolism , Protein Structure, Tertiary , Pyridines/pharmacology , RatsABSTRACT
4-Methylaminopyridine (4-MAP) (5) is a potent but nonselective nitric oxide synthase (NOS) inhibitor. While simple N-methylation in this series results in poor activity, more elaborate N-substitution such as with 4-piperidine carbamate or amide results in potent and selective inducible NOS inhibition. Evidently, a flipping of the pyridine ring between these new inhibitors allows the piperidine to interact with different residues and confer excellent selectivity.
