ABSTRACT
GPR40/FFAR1 is a G-protein-coupled receptor expressed in pancreatic ß-cells and enteroendocrine cells. GPR40 activation stimulates secretions of insulin and incretin, both of which are the pivotal regulators of glycemic control. Therefore, a GPR40 agonist is an attractive target for the treatment of type 2 diabetes mellitus. Using the reported biaryl derivative 1, we shifted the hydrophobic moiety to the terminal aryl ring and replaced the central aryl ring with piperidine, generating 2-(4,4-dimethylpentyl)phenyl piperidine 4a, which had improved potency for GPR40 and high lipophilicity. We replaced the hydrophobic moiety with N-alkyl-N-aryl benzamides to lower the lipophilicity and restrict the N-alkyl moieties to the presumed lipophilic pocket using the intramolecular π-π stacking of cis-preferential N-alkyl-N-aryl benzamide. Among these, orally available (3S)-3-cyclopropyl-3-(2-((1-(2-((2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid (SCO-267) effectively stimulated insulin secretion and GLP-1 release and ameliorated glucose tolerance in diabetic rats via GPR40 full agonism.
Subject(s)
Benzamides/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/therapeutic use , Piperidines/therapeutic use , Receptors, G-Protein-Coupled/agonists , Animals , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , CHO Cells , Cricetulus , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Male , Mice, Inbred ICR , Molecular Structure , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
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
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
An efficient divergent synthesis of L-sugars and L-iminosugars from D-sugars is described. The important intermediate, delta-hydroxyalkoxamate, prepared from D-glucono-/galactono-1,5-lactone, was cyclized under Mitsunobu conditions to give the O-cyclized oxime compound and the N-cyclized lactam compound as mixtures. A more detailed investigation revealed that the appropriate protecting groups and solvents controlled the specificity for the O-/N-cyclization of the delta-hydroxyalkoxamate. Suitable protection at the 6-position of delta-hydroxyalkoxamate, derived from D-glucono-1,5-lactone, afforded the corresponding O-alkylation product alone. Thus we succeeded in applying this to the total synthesis of L-iduronic acid. In contrast, with both TBDMS as the protecting group and RCN as the solvent the efficient conversion of D-glucono/galactono-1,5-lactone into the corresponding L-iminosugars (L-idonolactam and L-altronolactam) was achieved.
Subject(s)
Carbohydrates/chemical synthesis , Iduronic Acid/chemical synthesis , Imino Sugars/chemical synthesis , Carbohydrate Conformation , Carbohydrates/chemistry , Cyclization , Lactones/chemistry , Siloxanes/chemistry , Styrenes/chemistryABSTRACT
[reaction: see text] D-Mannono-1,4-lactone was efficiently converted into L-ribose in eight steps. A key step of this synthesis is the cyclization of a gamma-hydroxyalkoxamate under Mitsunobu conditions. It is noteworthy that the O-alkylation product was obtained in 94% yield and that none of the N-alkylation product was detected in this cyclization.