ABSTRACT
A new series of imidazopyridine CB2 agonists is described. Structural optimization improved CB2/CB1 selectivity in this series and conferred physical properties that facilitated high in vivo exposure, both centrally and peripherally. Administration of a highly selective CB2 agonist in a rat model of analgesia was ineffective despite substantial CNS exposure, while administration of a moderately selective CB2/CB1 agonist exhibited significant analgesic effects.
Subject(s)
Analgesics/chemistry , Pyridines/chemistry , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB2/agonists , Analgesics/chemical synthesis , Analgesics/therapeutic use , Animals , Disease Models, Animal , Freund's Adjuvant/pharmacology , Humans , Hyperalgesia/drug therapy , Pyridines/chemical synthesis , Pyridines/therapeutic use , Rats , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolismABSTRACT
This communication reports a new synthetic route of pyridopyrimidines to facilitate their structural optimization in a library fashion and describes the development of pyridopyrimidines that have excellent enzymatic and cell potency against Akt1 and Akt2. This series also shows a high level of selectivity over other closely related kinases and significantly improved caspase-3 activity with the more optimized compounds.
Subject(s)
Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Amines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Caspase 3/metabolism , Cell Line, Tumor , Dose-Response Relationship, Drug , Humans , Inhibitory Concentration 50 , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Structure-Activity Relationship , TNF-Related Apoptosis-Inducing Ligand/pharmacologyABSTRACT
This letter shows inhibitor SAR on a pyridine series of allosteric Akt inhibitors to optimize enzymatic and cellular potency. We have optimized 2,3,5-trisubstituted pyridines to give potent Akt1 and Akt2 inhibitors in both enzyme and cell based assays. In addition, we will also highlight the pharmacokinetic profile of an optimized inhibitor that has low clearance and long half-life in dogs.
Subject(s)
Allosteric Site , Prostatic Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Pyridines/chemistry , Animals , Apoptosis/drug effects , Caspases/metabolism , Dogs , Humans , Male , Metabolic Clearance Rate , Molecular Structure , Prostatic Neoplasms/metabolism , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins c-akt/metabolism , Structure-Activity Relationship , TNF-Related Apoptosis-Inducing Ligand/pharmacology , Tumor Cells, CulturedABSTRACT
Syntheses of the eight enantiomerically pure diastereomers of the 12-F(2)-isoprostanes (4-11) are described. The key steps included rhodium-mediated intramolecular cyclopropanation and enzymatic resolution of the racemic diol 12.
