ABSTRACT
A series of GPR119 agonists based on a 2,6-diazatricyclo[3.3.1.1â¼3,7â¼]decane ring system is described. Also provided is a detailed account of the development of a multigram scale synthesis of the diazatricyclic ring system, which was achieved using a Hofmann-Löffler-Freytag reaction as the key step. The basis for the use of this complex framework lies in an attempt to constrain one end of the molecule in the "agonist conformation" as was previously described for 3-oxa-7-aza-bicyclo[3.3.1]nonanes. Optimization of carbamate analogues of the diazatricylic compounds led to the identification of 32i as a potent agonist of the GPR119 receptor with low unbound human liver microsomal clearance. The use of an agonist response weighted ligand lipophilic efficiency (LLE) termed AgLLE is discussed along with the issues of applying efficiency measures to agonist programs. Ultimately, solubility limited absorption and poor exposure reduced further interest in these molecules.
Subject(s)
Aza Compounds/chemical synthesis , Bridged-Ring Compounds/chemical synthesis , Cyclodecanes/chemical synthesis , Receptors, G-Protein-Coupled/agonists , Animals , Aza Compounds/chemistry , Aza Compounds/pharmacology , Biological Availability , Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/pharmacology , Crystallography, X-Ray , Cyclodecanes/chemistry , Cyclodecanes/pharmacology , Dogs , Drug Design , Humans , Male , Microsomes, Liver/metabolism , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, G-Protein-Coupled/chemistry , Solubility , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The synthesis and properties of the bridged piperidine (oxaazabicyclo) compounds 8, 9, and 11 are described. A conformational analysis of these structures is compared with the representative GPR119 ligand 1. These results and the differences in agonist pharmacology are used to formulate a conformation-based hypothesis to understand activation of the GPR119 receptor. We also show for these structures that the agonist pharmacology in rat masks the important differences in human pharmacology.
