ABSTRACT
A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Oxadiazoles/chemical synthesis , Animals , Diabetes Mellitus/drug therapy , Diacylglycerol O-Acyltransferase/metabolism , Dogs , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Half-Life , High-Throughput Screening Assays , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Ligands , Mice , Obesity/drug therapy , Oxadiazoles/pharmacokinetics , Quantitative Structure-Activity Relationship , RatsSubject(s)
BCG Vaccine , Dairying , Milk/microbiology , Tuberculosis/prevention & control , Animals , Cattle , Child , Humans , Mycobacterium bovis/pathogenicity , Tuberculosis/transmissionABSTRACT
The reaction of lithiated trimethylsilyldiazomethane (LTMSD) with aldehydes and subsequent quenching with TMSCl furnished relatively stable alpha-silylated diazocompounds. Upon treatment of the alpha-silylated diazocompounds with Rh2(OAc)4 in refluxing toluene, alpha-silyl silyl enol ethers were formed from unbranched and branched aliphatic aldehydes through predominantly 1,2-migration of the C-H bond. In contrast, treatment of the alpha-silylated diazocompounds with Rh2(tfa)4 at room temperature gave alpha-silyl silyl enol ethers through exclusive and unusual 1,2-migration of the C-C bond. The origin of the selectivity observed from the two catalysts is discussed in relation to early and late transition states.
ABSTRACT
Tosylhydrazones derived from aryl aldehydes react with t-BuOK, ClFeTPP, (MeO)3P, and aldehydes to furnish olefins with high E selectivity. These reactions occur through a Wittig-type pathway via the corresponding diazo compounds, metal carbenes and phosphorous ylides, with the water-soluble trimethyl phosphate as the byproduct. Similar reactions can also be performed using ethyl diazoacetate; however, high E selectivity was only observed in the presence of LiBr. In this case, the reaction is believed to occur via the phosphonate anion, formed through an Arbuzov reaction. Thus this olefination reaction occurs through a Horner-Wadsworth-Emmons (HWE) reaction but the phosphonate anion is generated under completely base-free conditions.
ABSTRACT
The reaction of lithium (trimethylsilyl)diazomethane with aldehydes and ketones has been investigated, and it has been found that quenching at low temperature with MeOH followed by addition of Rh2(OAc)4 gave silyl enol ethers in high yields. Quenching with other electrophiles (e.g., deuterium, MeI) gave terminal and substituted silyl enol ethers with complete control over regio- and stereochemistry. The mechanism of this novel process has been mapped out through a combination of deuterium labeling, ReactIR, and isolation of reaction intermediates.
