ABSTRACT
A previous disclosure from this lab highlighted the discovery of pyridyl amides as potent 11ß-HSD1 inhibitors. In order to build additional novelty and polarity into this chemotype, replacement of the hydrogen-bonding carbonyl (CO) pharmacophore with the bioisosteric sulfonyl (SO2) group was examined. Despite initial comparisons suggesting the corresponding sulfonamides exhibited weaker activity versus their carbonyl counterparts, further optimization was performed in an effort to identify various potent and unique leads for the program. Judicious incorporation of polar moieties resulted in the identification of compounds with enhanced potency and lipophilicity profiles, resulting in leads with superior aqueous solubility and liver microsomal stability.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Metabolic Diseases/drug therapy , Sulfonamides/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 2/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism , Binding Sites , Drug Evaluation, Preclinical , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/therapeutic use , Humans , Microsomes, Liver/metabolism , Molecular Docking Simulation , Protein Binding , Protein Structure, Tertiary , Structure-Activity Relationship , Sulfonamides/metabolism , Sulfonamides/therapeutic useABSTRACT
Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11ß-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads.
