ABSTRACT
A potent, in vivo efficacious 11ß hydroxysteroid dehydrogenase type 1 (11ß HSD1) inhibitor (11j) has been identified. Compound 11j inhibited 11ß HSD1 activity in human adipocytes with an IC50 of 4.3nM and in primary human adipose tissue with an IC80 of 53nM. Oral administration of 11j to cynomolgus monkey inhibited 11ß HSD1 activity in adipose tissue. Compound 11j exhibited >1000× selectivity over other hydroxysteroid dehydrogenases, displays desirable pharmacodynamic properties and entered human clinical trials in 2011.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Oxazines/chemistry , Pyridones/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Adipose Tissue/cytology , Adipose Tissue/metabolism , Administration, Oral , Animals , Binding Sites , Cells, Cultured , Cytochrome P-450 Enzyme System/metabolism , Drug Evaluation, Preclinical , Half-Life , Inhibitory Concentration 50 , Macaca fascicularis , Molecular Docking Simulation , Oxazines/administration & dosage , Oxazines/pharmacokinetics , Protein Structure, Tertiary , Pyridones/administration & dosage , Pyridones/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
Liver X receptor (LXR) agonists have been reported to lower brain amyloid beta (Aß) and thus to have potential for the treatment of Alzheimer's disease. Structure and property based design led to the discovery of a series of orally bioavailable, brain penetrant LXR agonists. Oral administration of compound 18 to rats resulted in significant upregulation of the expression of the LXR target gene ABCA1 in brain tissue, but no significant effect on Aß levels was detected.
Subject(s)
Brain/metabolism , Liver X Receptors/drug effects , ATP Binding Cassette Transporter 1/genetics , ATP Binding Cassette Transporter 1/metabolism , Animals , Male , RNA, Messenger/genetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Up-RegulationABSTRACT
This article describes the application of Contour to the design and discovery of a novel, potent, orally efficacious liver X receptor ß (LXRß) agonist (17). Contour technology is a structure-based drug design platform that generates molecules using a context perceptive growth algorithm guided by a contact sensitive scoring function. The growth engine uses binding site perception and programmable growth capability to create drug-like molecules by assembling fragments that naturally complement hydrophilic and hydrophobic features of the protein binding site. Starting with a crystal structure of LXRß and a docked 2-(methylsulfonyl)benzyl alcohol fragment (6), Contour was used to design agonists containing a piperazine core. Compound 17 binds to LXRß with high affinity and to LXRα to a lesser extent, and induces the expression of LXR target genes in vitro and in vivo. This molecule served as a starting point for further optimization and generation of a candidate which is currently in human clinical trials for treating atopic dermatitis.
Subject(s)
Benzylamines/chemistry , Drug Design , Drug Discovery , Orphan Nuclear Receptors/agonists , Piperazines/chemistry , Pyrimidines/chemistry , Pyrimidines/metabolism , Sulfones/chemistry , Sulfones/metabolism , Binding Sites , Crystallography, X-Ray , Humans , Liver X Receptors , Structure-Activity RelationshipABSTRACT
Synthesis of 2-adamantyl carbamate derivatives of piperidines and pyrrolidines led to the discovery of 9a with an IC(50) of 15.2 nM against human 11ß-HSD1 in adipocytes. Optimization for increased adipocyte potency, metabolic stability and selectivity afforded 11k and 11l, both of which were >25% orally bioavailable in rat.
