ABSTRACT
The synthesis and antibacterial activity of heterocyclic methylsulfone hydroxamates is presented. Compounds in this series are potent inhibitors of the LpxC enzyme, a key enzyme involved in the production of lipopolysaccharide (LPS) found in the outer membrane of Gram-negative bacteria. SAR evaluation of compounds in this series revealed analogs with potent antibacterial activity against challenging Gram-negative species such as Pseudomonas aeruginosa and Klebsiella pneumoniae.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/chemistry , Enzyme Inhibitors/chemistry , Gram-Negative Bacteria/drug effects , Hydroxamic Acids/chemistry , Amidohydrolases/metabolism , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds/chemistry , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacology , Klebsiella pneumoniae/drug effects , Microbial Sensitivity Tests , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/enzymology , Structure-Activity Relationship , Sulfones/chemistryABSTRACT
An efficient method was developed for the synthesis of 2-methylene-4-substituted ethyl butyrates via cyclopropyl opening followed by a Wittig reaction. The desired products were formed in a two-step, one-pot reaction sequence. Alternatively, the key intermediate ylide 2 was isolable and could be stored under oxygen-free conditions and subsequently utilized. A variety of nucleophiles were found to open the commercially available cyclopropane 1. The resulting ylide reacted with aldehydes to provide E-olefinic products.
Subject(s)
Borates/chemistry , Organophosphorus Compounds/chemistry , Aldehydes/chemistry , Cyclization , Molecular StructureABSTRACT
We describe the design, synthesis, and structure-activity relationships of triazolobenzodiazepinone CCK1 receptor agonists. Analogs in this series demonstrate potent agonist activity as measured by in vitro and in vivo assays for CCK1 agonism. Our efforts resulted in the identification of compound 4a which significantly reduced food intake with minimal systemic exposure in rodents.
Subject(s)
Anti-Obesity Agents/pharmacology , Benzodiazepines/pharmacology , Receptors, Cholecystokinin/agonists , Animals , Anti-Obesity Agents/pharmacokinetics , Benzodiazepines/chemistry , Benzodiazepines/pharmacokinetics , Male , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The development of a series of novel 1,2,3,4-tetrahydroisoquinolin-1-ones as antagonists of G protein-coupled receptor 40 (GPR40) is described. The synthesis, in vitro inhibitory values for GPR40, in vitro microsomal clearance and rat in vivo clearance data are discussed. Initial hits displayed high rat in vivo clearances that were higher than liver blood flow. Optimization of rat in vivo clearance was achieved and led to the identification of 15i, whose rat oral pharmacokinetic data is reported.
Subject(s)
Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, G-Protein-Coupled/chemistry , Tetrahydroisoquinolines/chemical synthesis , Tetrahydroisoquinolines/pharmacokinetics , Administration, Oral , Animals , Chemistry, Pharmaceutical/methods , Drug Design , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Ligands , Metabolic Clearance Rate , Models, Chemical , Rats , Structure-Activity Relationship , Tetrahydroisoquinolines/chemistryABSTRACT
A series of 2-heteroaryl-4-arylimidazoles with potent in vitro activity at the NPY5 receptor was developed. Introduction of electron-withdrawing groups on the 4-aryl ring led to a significant improvement of in vitro potency. Several analogues from this series had anorectic activity in rodent feeding models, but were also found to have undesired behavioral effects in spontaneous locomotor activity.
Subject(s)
Imidazoles/chemistry , Imidazoles/pharmacology , Receptors, Neuropeptide Y/antagonists & inhibitors , Animals , Behavior, Animal/drug effects , Feeding Behavior/drug effects , Rats , Structure-Activity RelationshipABSTRACT
Beginning with carbazole 1a, the amide and alkyl substituents were optimized to maintain potency while adding solubilizing groups. Efforts to replace the 3-amino-9-ethylcarbazole core, a known carcinogen, used the SAR generated in the carbazole series for guidance and led to the synthesis of a number of core-modified analogues. In addition, an isosteric series, in which the amide was replaced with an imidazole, was prepared. Two potent new series lacking the putative toxicophore were identified from these endeavors.
Subject(s)
Amides/chemistry , Amides/pharmacology , Carbazoles/chemistry , Carbazoles/pharmacology , Receptors, Neuropeptide Y/antagonists & inhibitors , Animals , Calcium/chemistry , Calcium/pharmacology , Eating/drug effects , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Inhibitory Concentration 50 , Male , Radioligand Assay , Rats , Rats, Sprague-Dawley , Solubility , Structure-Activity RelationshipABSTRACT
To investigate the anorectic potential of NPY5 receptor antagonists, we have profiled the in vitro and in vivo properties of 3-[2-[6-(2-tert-butoxyethoxy)pyridin-3-yl]-1H-imidazol-4-yl]benzonitrile hydrochloride salt (1). This compound was found to have excellent NPY5 receptor affinity and selectivity, potent functional antagonism, and good peripheral and central nervous system exposure in rats. This compound attenuated bovine pancreatic polypeptide induced food intake in rats but failed to demonstrate anorectic activity in rodent natural feeding models.
