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
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
A series of diazepinylbenzoic acid derivatives were synthesized and tested in the inhibition assay of the transactivation of RXR. Oral treatment of cyano derivatives (16f) was found to show anti-diabetic and anti-obesity effects in KK-A(y) mice.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Retinoid X Receptor alpha/antagonists & inhibitors , Retinoid X Receptor alpha/chemistry , Retinoid X Receptor alpha/chemical synthesis , Animals , Anti-Obesity Agents/pharmacology , Body Weight , Dietary Fats , Drug Design , Hypoglycemic Agents/pharmacology , Inhibitory Concentration 50 , Male , Mice , Mice, Transgenic , Models, Chemical , Structure-Activity Relationship , Transcriptional ActivationABSTRACT
Synthesis and structure-activity relationship of RXR antagonists employing a diazepinylbenzoic acid scaffold are described. Of those antagonists, sulfonamide derivatives (6v and 6w) reveal a high antagonistic activity and good pharmacokinetic properties.
Subject(s)
Benzoates/chemistry , Benzoates/chemical synthesis , Biphenyl Compounds/chemistry , Biphenyl Compounds/chemical synthesis , Chemistry, Pharmaceutical/methods , Receptors, Retinoic Acid/antagonists & inhibitors , Receptors, Retinoic Acid/chemistry , Administration, Oral , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Structure , Retinoic Acid Receptor alpha , Structure-Activity Relationship , Time Factors , Trans-Activators , Transcription Factors/chemistry , Transcriptional ActivationABSTRACT
Direct beta-glucosidation between 1,6-octanediol (5) and D-glucose (3) using the immobilized beta-glucosidase (EC 3.2.1.21) from almonds with the synthetic prepolymer ENTP-4000 gave a mono-beta-glucoside (6) in 61.4% yield, which was converted into the n-hexyl beta-D-glucopyranoside (1) by means of a chemoenzymatic method. The coupling of the n-hexyl beta-D-glucopyranoside congener (13) and 2,3,4-tri-O-acetyl-beta-D-xylosyl congener (14), followed by deprotection, afforded the synthetic n-hexyl O-beta-D-xylopyranosyl-(1-->6)-beta-D-glucopyranoside (2), which was identical to the natural 2 with respect to the spectral data and specific rotation.
