2-Trifluoromethyl-4-aminobenzimidazoles were previously identified by screening to be active antagonists of the gonadotropin releasing hormone receptor (GnRH-R). Structure activity relationships and diversity oriented synthesis are shown here in greater detail. 2-Substituted benzimidazoles were synthesized in parallel by the coupling of carboxylic acids with a latent intermediate diamine monomer to yield the desired benzimidazoles in fair yields. A catch and release strategy was employed as a product isolation technique, followed by RP-HPLC to obtain products of desired purity for biological evaluation. Two libraries were prepared and screened to determine the optimal substitution for inhibitory activity against GnRH-R. The initial library focused on substituted phenyl, pyridine, and thiophenes. The follow-up library focused on substitution patterns observed in the initial library members and generated compounds with IC(50) values lower than 100 nM at the GnRH-R.
Benzimidazoles/chemical synthesis , Gonadotropin-Releasing Hormone/antagonists & inhibitors , Hormone Antagonists/chemical synthesis , Benzimidazoles/pharmacology , Carboxylic Acids/chemistry , Combinatorial Chemistry Techniques , Diamines/chemistry , Hormone Antagonists/pharmacology , Inhibitory Concentration 50 , Small Molecule Libraries/chemical synthesis , Structure-Activity Relationship
A series of potent and binding selective LXRbeta agonists was developed using the previously reported non-selective LXR ligand WAY-254011 as a structural template. With the aid of molecular modeling, it was found that 2,3-diMe-Ph, 2,5-diMe-Ph, and naphthalene substituted quinoline acetic acids (such as quinoline 33, 37, and 38) showed selectivity for LXRbeta over LXRalpha in binding assays.
Carboxylic Acids/chemistry , Carboxylic Acids/metabolism , DNA-Binding Proteins/agonists , Quinolines/chemistry , Quinolines/metabolism , Receptors, Cytoplasmic and Nuclear/agonists , Animals , Carboxylic Acids/pharmacology , Crystallography, X-Ray , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism , Gene Expression , Humans , Ligands , Liver X Receptors , Macrophages/drug effects , Macrophages/metabolism , Mice , Models, Molecular , Orphan Nuclear Receptors , Quinolines/pharmacology , Receptors, Cytoplasmic and Nuclear/chemistry , Receptors, Cytoplasmic and Nuclear/metabolism , Substrate Specificity , Transcriptional Activation