ABSTRACT
The synthesis of a novel gut selective MTP inhibitor, 5-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide (dirlotapide), and its in vitro and in vivo profile are described. Dirlotapide (3) demonstrated excellent potency against MTP enzyme in HepG2 cells and canine hepatocytes. This novel MTP inhibitor also showed excellent efficacy when tested in a canine food intake model.
Subject(s)
Carbamates/chemical synthesis , Carboxylic Acids/chemistry , Carboxylic Acids/chemical synthesis , Carrier Proteins/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Indoles/chemical synthesis , Obesity/drug therapy , Animals , Carbamates/chemistry , Carbamates/pharmacology , Carboxylic Acids/pharmacology , Dogs , Drug Design , Drug Evaluation, Preclinical , Humans , Hydrogen-Ion Concentration , In Vitro Techniques , Indoles/chemistry , Indoles/pharmacology , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , RatsABSTRACT
We have successfully identified a number of novel MTP inhibitors with single digit nanomolar potency. Analogues 10aq and 10dq demonstrated in vivo efficacy in a murine gut retention assay.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacology , Carrier Proteins/antagonists & inhibitors , Administration, Oral , Animals , Anti-Obesity Agents/administration & dosage , Anti-Obesity Agents/chemistry , Carrier Proteins/metabolism , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
The discovery of heteroaryl-phenyl-substituted pyrazole derivatives as canine selective COX-2 inhibitors is described. Structure-activity relationship (SAR) studies of this class of compounds led to the identification of compound 1 which demonstrated a canine whole blood COX-2 inhibitory IC50 of 12 nM and selectivity ratio of COX-1/COX-2 greater than 4000-fold.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemical synthesis , Pyrazoles/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/pharmacology , Dogs , Inhibitory Concentration 50 , Pyrazoles/pharmacology , Structure-Activity RelationshipABSTRACT
The synthesis of a novel canine COX-2 selective inhibitor, 2-(3-difluoromethyl-5-phenylpyrazol-1-yl)-5-methanesulfonylpyridine, and its in vitro and in vivo profile are described. Pyrazole 8 demonstrated excellent potency and selectivity for canine COX-2 in both in vitro and ex vivo whole blood assays. This novel COX-2 inhibitor also showed a good pharmacokinetic profile (pk) following oral (po), intravenous (iv), and subcutaneous (sc) dosing and demonstrated excellent in vivo efficacy in a canine synovitis model.
Subject(s)
Cyclooxygenase Inhibitors/pharmacology , Prostaglandin-Endoperoxide Synthases/drug effects , Pyrazoles/pharmacology , Pyridines/pharmacology , Animals , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Dogs , In Vitro Techniques , Magnetic Resonance Spectroscopy , Pyrazoles/chemical synthesis , Pyridines/chemical synthesisABSTRACT
Structure-activity relationship (SAR) studies of 2-[3-di(and tri)fluoromethyl-5-arylpyrazol-1-yl]-5-methanesulfonylpyridine derivatives for canine COX enzymes are described. This led to the identification of 12a as a lead candidate for further progression. The in vitro and in vivo activity of 12a for the canine COX-2 enzyme as well as its in vivo efficacy and pharmacokinetic properties in dog are highlighted.
Subject(s)
Cyclooxygenase Inhibitors/administration & dosage , Cyclooxygenase Inhibitors/chemistry , Isoenzymes/antagonists & inhibitors , Pyridines/administration & dosage , Pyridines/chemistry , Administration, Oral , Animals , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Dogs , Isoenzymes/metabolism , Prostaglandin-Endoperoxide Synthases/metabolism , Structure-Activity RelationshipABSTRACT
Modification of the cladinose C-4" position via manipulation of the corresponding keto derivatives afforded two stereochemically pure series of compounds. The synthesis and structure determination of these compounds is described within. The in vitro and in vivo biological activity of this novel series of C-4" modified macrolides is also described.
Subject(s)
Aza Compounds/chemical synthesis , Aza Compounds/pharmacology , Macrolides/chemical synthesis , Macrolides/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Aza Compounds/chemistry , Disease Models, Animal , Escherichia coli/drug effects , Hexoses/chemistry , Macrolides/chemistry , Mice , Microbial Sensitivity Tests , Molecular Conformation , Pasteurella Infections/microbiology , Pasteurella multocida/drug effects , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The stereoselective synthesis of two novel series of tribasic macrocyclic antibiotics with potent in vitro activity against Pasteurella multocida and Escherichia coli strains of bacteria is described. The in vitro activity can be significantly influenced by the nature of the substituents on the C-4" aminoalcohol, with the stereochemistry of the C-4" alcohol playing a less critical role. The effect of substitution and stereochemistry on the in vivo activity in a murine model of respiratory infection is also described.
