ABSTRACT
Seeking compounds preferentially potent and selective for MMP-13, we reported in the preceding Letter on a series of hydroxamic acids with a flexible benzamide tail groups.(1a) Here, we replace the amide moiety with non-hydrolyzable heterocycles in an effort to improve half-life. We identify a hydroxamate tetrazole 4e that spares MMP-1 and -14, shows >400-fold selectivity versus MMP-8 and >600-fold selectivity versus MMP-2, and has a 4.8 h half-life in rats. X-ray data (1.9 Å) for tetrazole 4c is presented.
Subject(s)
Amides/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Sulfones/chemical synthesis , Amides/chemistry , Animals , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Heterocyclic Compounds/chemistry , Hydroxamic Acids/chemistry , Matrix Metalloproteinase 13/chemistry , Models, Molecular , Rats , Structure-Activity Relationship , Substrate Specificity , Sulfones/chemistryABSTRACT
We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R-4g with a wide range of substituents at each position of the pyrazoline ring resulted in R-12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3S,3aR-27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3S,3aR-27d was advanced to clinical studies.
Subject(s)
Antihypertensive Agents/chemical synthesis , Hypertension/drug therapy , Indazoles/chemical synthesis , Kidney Diseases/drug therapy , Mineralocorticoid Receptor Antagonists , Nitriles/chemical synthesis , Animals , Antihypertensive Agents/pharmacokinetics , Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Cell Line, Tumor , Chlorobenzenes , Crystallography, X-Ray , Humans , Indazoles/pharmacokinetics , Indazoles/pharmacology , Indenes , Male , Models, Molecular , Molecular Conformation , Nitriles/pharmacokinetics , Nitriles/pharmacology , Radioligand Assay , Rats , Rats, Inbred Dahl , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of phenyl piperidine alpha-sulfone hydroxamate derivatives has been prepared utilizing a combination of solution-phase and resin-bound library technologies to afford compounds that are potent and highly selective for MMP-13, are dual-sparing of MMP-1 and MMP-14 (MT1-MMP) and exhibit oral bioavailability in rats.
Subject(s)
Matrix Metalloproteinase Inhibitors , Administration, Oral , Animals , Biological Availability , Hydroxamic Acids/administration & dosage , Matrix Metalloproteinase 1/drug effects , Matrix Metalloproteinase 14/drug effects , Piperidines , Rats , Small Molecule Libraries , Solubility , Substrate Specificity , SulfonesABSTRACT
A series of N-aryl isonipecotamide alpha-sulfone hydroxamate derivatives has been prepared utilizing a combination of solution-phase and resin-bound library technologies to afford compounds that are potent and highly selective for MMP-13.
