ABSTRACT
A cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a high-throughput screening hit from a target-family tailored library. Optimization of both the prime and the nonprime site residues flanking the central piperidine transition-state surrogate resulted in analogues with improved potency and pharmacokinetic (PK) properties, culminating in the identification of the 4-hydroxy-3,5-substituted piperidine 31. This compound showed high in vitro potency toward human renin with excellent off-target selectivity, 60% oral bioavailability in rat, and dose-dependent blood pressure lowering effects in the double-transgenic rat model.
ABSTRACT
We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.
Subject(s)
Cathepsins/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Administration, Oral , Animals , Brain/drug effects , Cathepsin L , Combinatorial Chemistry Techniques , Cysteine Endopeptidases , Humans , Male , Molecular Structure , Multiple Sclerosis/drug therapy , Pain/drug therapy , Pyrimidines/blood , Pyrimidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
On the basis of the pyrrolopyrimidine core structure that was previously discovered, cathepsin K inhibitors having a spiro amine at the P3 have been explored to enhance the target, bone marrow, tissue distribution. Several spiro structures were identified with improved distribution toward bone marrow. The representative inhibitor 7 of this series revealed in vivo reduction in C-terminal telopeptide of type I collagen in rats and monkeys.
Subject(s)
Bone Resorption/drug therapy , Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacokinetics , Animals , Bone Marrow/metabolism , Cathepsin K , Collagen Type I/metabolism , Haplorhini , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Rats , Spiro Compounds , Tissue DistributionABSTRACT
Cathepsin S inhibitors are well-known to be an attractive target as immunological therapeutic agents. Recently, our gene expression analysis identified that cathepsin S inhibitors could also be effective for neuropathic pain. Herein, we describe the efficacy of selective cathepsin S inhibitors as antihyperalgesics in a model of neuropathic pain in rats after oral administration.
Subject(s)
Analgesics/therapeutic use , Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/therapeutic use , Peripheral Nervous System Diseases/drug therapy , Administration, Oral , Analgesics/administration & dosage , Analgesics/pharmacokinetics , Animals , Biological Availability , Cysteine Proteinase Inhibitors/administration & dosage , Cysteine Proteinase Inhibitors/pharmacokinetics , Peripheral Nervous System Diseases/enzymology , RatsABSTRACT
We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine.
Subject(s)
Cathepsins/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Cysteine Proteinase Inhibitors/chemical synthesis , Nitriles/chemical synthesis , Peptides/chemistry , Pyrimidines/chemistry , Pyrimidines/chemical synthesis , Animals , Cysteine Proteinase Inhibitors/pharmacology , Drug Design , Humans , Inhibitory Concentration 50 , Male , Molecular Conformation , Nitriles/pharmacology , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Recombinant Proteins/chemistry , Structure-Activity RelationshipABSTRACT
Nonpeptidic, selective, and potent cathepsin S inhibitors were derived from an in-house pyrrolopyrimidine cathepsin K inhibitor by modification of the P2 and P3 moieties. The pyrrolopyrimidine-based inhibitors show nanomolar inhibition of cathepsin S with over 100-fold selectivity against other cysteine proteases, including cathepsin K and L. Some of the inhibitors showed cellular activities in mouse splenocytes as well as oral bioavailabilities in rats.
Subject(s)
Cathepsins/antagonists & inhibitors , Cysteine Endopeptidases/chemical synthesis , Cysteine Proteinase Inhibitors/chemical synthesis , Biological Availability , Cathepsin K , Cathepsin L , Cathepsins/chemistry , Chemistry, Pharmaceutical , Cysteine Endopeptidases/chemistry , Cysteine Proteinase Inhibitors/pharmacology , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Molecular Structure , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
Cyano pyrimidine acetylene and cyano pyrimidine t-amine, which belong to a new chemical class, were prepared and tested for inhibitory activities against cathepsin K and the highly homologous cathepsins L and S. The use of novel chemotypes in the development of cathepsin K inhibitors has been demonstrated by derivatives of compounds 1 and 8.
Subject(s)
Cathepsins/antagonists & inhibitors , Cathepsins/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Binding Sites , Cathepsin K , Cathepsin L , Cathepsins/chemistry , Cysteine Endopeptidases/metabolism , Drug Design , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Pyrrolopyrimidine, a novel scaffold, allows to adjust interactions within the S3 subsite of cathepsin K. The core intermediate 10 facilitated the P3 optimization and identified highly potent and selective cathepsin K inhibitors 11-20.
Subject(s)
Cathepsins/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Cathepsin K , Humans , Inhibitory Concentration 50 , Molecular Structure , Pyrimidines/chemistry , Pyrroles/chemistry , Recombinant Proteins/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
Starting from the purine lead structure 1, a new series of cathepsin K inhibitors based on a pyrimidine scaffold have been explored. Investigations of P3 and P2 substituents based on molecular modeling suggestions resulted in potent cathepsin K inhibitors with an improved selectivity profile over other cathepsins.
