ABSTRACT
A series of cyclopropyl hydroxamic acids were prepared. Many of the compounds displayed picomolar affinity for the TACE enzyme while maintaining good to excellent selectivity profiles versus MMP-1, -2, -3, -7, -14, and ADAM-10. X-ray analysis of an inhibitor in the TACE active site indicated that the molecules bound to the enzyme in the S1'-S3' pocket.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Hydroxamic Acids/pharmacology , Protease Inhibitors/pharmacology , ADAM17 Protein , Animals , Area Under Curve , Biological Availability , Drug Discovery , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacokinetics , Models, Molecular , Protease Inhibitors/pharmacokinetics , Rats , Rats, Sprague-DawleyABSTRACT
Structure-activity relationship on our recently reported triaryl bis-sulfone class of cannabinoid-2 (CB2) receptor selective inverse agonists was explored. Modifications to the methane sulfonamide, substitutions to B and C phenyl rings, and replacements of the C-ring were investigated. A compound with excellent CB2 activity, selectivity for CB2 over CB1, and in vivo plasma levels was identified.
Subject(s)
Chemistry, Pharmaceutical/methods , Receptor, Cannabinoid, CB2/chemistry , Sulfones/chemistry , Animals , Drug Design , Drug Evaluation, Preclinical , Kinetics , Ligands , Models, Chemical , Protein Binding , Rats , Receptors, Drug , Sodium/chemistry , Structure-Activity RelationshipABSTRACT
We recently reported that compound 1 is a potent inhibitor of the CB2 receptor with high selectivity over CB1. This paper describes the SAR development for this class of compounds. Variation of the substitution pattern on the aromatic rings, as well as the groups linking them together, led to sub-nanomolar inhibitors of the CB2 receptor, with high selectivity over CB1.
Subject(s)
Receptor, Cannabinoid, CB2/metabolism , Sulfones/metabolism , Ligands , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
By employing a stereosimplification approach, a thorough SAR exploration of the piperidine region of Sch 206272 was possible through a practical and efficient synthesis of substituted cyclic ureas. This SAR study led to the identification of a benzimidazolinone series of compounds which display single digit nanomolar NK(1)/NK(2) affinity and near micromolar binding for the NK(3) receptor.
Subject(s)
Oximes/chemistry , Receptors, Tachykinin/antagonists & inhibitors , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Neurokinin-1 Receptor Antagonists , Oximes/pharmacology , Receptors, Neurokinin-2/antagonists & inhibitors , Receptors, Neurokinin-3/antagonists & inhibitors , Sensitivity and Specificity , Structure-Activity RelationshipABSTRACT
A thorough SAR study of the oxime region of the dual NK(1)/NK(2) antagonist 1 revealed several modifications that result in potent dual antagonists. Follow up SAR studies on a second-generation scaffold demonstrate that certain polar groups on the oxime can improve the dual binding affinity to the subnanomolar range.
