ABSTRACT
A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARß, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARß (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens.
Subject(s)
Aminobenzoates/chemistry , Benzoates/chemistry , Drug Design , Retinoic Acid Receptor alpha/agonists , Tetrahydronaphthalenes/chemistry , Administration, Oral , Aminobenzoates/pharmacokinetics , Aminobenzoates/toxicity , Animals , Benzoates/pharmacokinetics , Benzoates/toxicity , COS Cells , Cell Survival/drug effects , Chlorocebus aethiops , Half-Life , Hep G2 Cells , Humans , Mice , Microsomes, Liver/metabolism , Rats , Receptors, Retinoic Acid/agonists , Receptors, Retinoic Acid/metabolism , Retinoic Acid Receptor alpha/metabolism , Structure-Activity Relationship , Tetrahydronaphthalenes/pharmacokinetics , Tetrahydronaphthalenes/toxicity , Retinoic Acid Receptor gammaABSTRACT
Methyleneaziridines can be converted into a wide range of 1,2-diamines and 2-cyanopiperidines in a single operation with the formation of three intermolecular carbon-carbon bonds using a "hybrid" MCR.
Subject(s)
Cyanides/chemistry , Diamines/chemical synthesis , Nitriles/chemical synthesis , Piperidines/chemical synthesis , Aziridines/chemistry , Carbon/chemistry , Combinatorial Chemistry Techniques , Cyclization , Methane/analogs & derivatives , Models, Chemical , Molecular StructureABSTRACT
Intramolecular nucleophilic substitution of the C-Br bond of (E)- and (Z)-2-bromobut-2-enylamines by the pendant nitrogen atom leads to 2-ethyleneaziridines by way of stereochemical inversion at the vinylic carbon atom. The stereochemistry of the products is unambiguously established by X-ray crystallography performed on two derivatives. These cyclizations represent some of the first examples of substitution with inversion in unactivated vinylic substrates. In conjunction with additional deuterium-labeling experiments, the accepted mechanism for this reaction is shown to be flawed.
