ABSTRACT
The metalloprotease ADAMTS-5 is considered a potential target for the treatment of osteoarthritis. To identify selective inhibitors of ADAMTS-5, we employed encoded library technology (ELT), which enables affinity selection of small molecule binders from complex mixtures by DNA tagging. Selection of ADAMTS-5 against a four-billion member ELT library led to a novel inhibitor scaffold not containing a classical zinc-binding functionality. One exemplar, (R)-N-((1-(4-(but-3-en-1-ylamino)-6-(((2-(thiophen-2-yl)thiazol-4-yl)methyl)amino)-1,3,5-triazin-2-yl)pyrrolidin-2-yl)methyl)-4-propylbenzenesulfonamide (8), inhibited ADAMTS-5 with IC(50) = 30 nM, showing >50-fold selectivity against ADAMTS-4 and >1000-fold selectivity against ADAMTS-1, ADAMTS-13, MMP-13, and TACE. Extensive SAR studies showed that potency and physicochemical properties of the scaffold could be further improved. Furthermore, in a human osteoarthritis cartilage explant study, compounds 8 and 15f inhibited aggrecanase-mediated (374)ARGS neoepitope release from aggrecan and glycosaminoglycan in response to IL-1ß/OSM stimulation. This study provides the first small molecule evidence for the critical role of ADAMTS-5 in human cartilage degradation.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Cartilage, Articular/drug effects , Databases, Chemical , Osteoarthritis/pathology , Sulfonamides/chemical synthesis , Triazines/chemical synthesis , ADAMTS5 Protein , Aggrecans/metabolism , Animals , Cartilage, Articular/metabolism , Cartilage, Articular/pathology , Endopeptidases/metabolism , Epitopes , Glycosaminoglycans/metabolism , Humans , In Vitro Techniques , Male , Middle Aged , Osteoarthritis/drug therapy , Rats , Rats, Sprague-Dawley , Small Molecule Libraries , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Triazines/pharmacokinetics , Triazines/pharmacologyABSTRACT
A full account of studies that culminated in the total synthesis of both antipodes and the assignment of its absolute configuration of Saudin, a hypoglycemic natural product. Two approaches are described, the first proceeding though bicyclic lactone intermediates and related second monocyclic esters. The former was obtained via asymmetric Diels-Alder cycloaddition and the latter by an asymmetric annulation protocol. Both approaches employ a Lewis acid promoted Claisen rearrangement, with the successful approach taking advantage of bidentate chelation to control the facial selectivity of the key Claisen rearrangement.
ABSTRACT
High throughput screening of our compound collection led to the discovery of a novel series of N-alkyl-5H-pyrido[4,3-b]indol-1-amines as urotensin-II receptor antagonists. Synthesis, initial structure and activity relationships, functional and animal ortholog activities of the series are described.
Subject(s)
Amines/chemical synthesis , Amines/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Urotensins/antagonists & inhibitors , Amines/chemistry , Animals , Combinatorial Chemistry Techniques , Mice , Molecular Structure , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
Aminomethylpiperazines, reported previously as being kappa-opioid receptor agonists, were identified as lead compounds in the development of selective urotensin receptor antagonists. Optimized substitution of the piperazine moiety has provided high affinity urotensin receptor antagonists with greater than 100-fold selectivity over the kappa-opioid receptor. Select compounds were found to inhibit urotensin-induced vasoconstriction in isolated rat aortic rings consistent with the hypothesis that an urotensin antagonist may be useful for the treatment of hypertension.
Subject(s)
Chemistry, Pharmaceutical/methods , Piperazines/pharmacology , Receptors, Opioid, kappa/antagonists & inhibitors , Taurine/analogs & derivatives , Urotensins/antagonists & inhibitors , Acamprosate , Animals , Aorta/metabolism , Drug Design , Humans , Hypertension/drug therapy , Models, Chemical , Piperazines/chemistry , Rats , Structure-Activity Relationship , Taurine/drug effectsABSTRACT
Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in compound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between stereochemistry and selectivity for hUT over the kappa-opioid receptor was also explored.
Subject(s)
Chemistry, Pharmaceutical/methods , Urotensins/antagonists & inhibitors , Administration, Oral , Animals , Brain/metabolism , Chromatography, High Pressure Liquid , Diamines/chemistry , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Rats , Receptors, Opioid, kappa/chemistry , Stereoisomerism , Structure-Activity Relationship , Urotensins/chemistryABSTRACT
This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-[3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities.
Subject(s)
Aniline Compounds/pharmacology , Piperidones/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Administration, Oral , Aniline Compounds/chemical synthesis , Aniline Compounds/chemistry , Animals , Biological Availability , Cell Line , Drug Evaluation, Preclinical , Humans , Molecular Structure , Molecular Weight , Piperidones/chemical synthesis , Piperidones/chemistry , Rats , Small Molecule Libraries , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of 2-aminomethyl piperidines has been discovered as novel urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that resulted in the identification of potent, cross-species active, and functional urotensin-II receptor antagonists such as 1a and 11a are described.
