ABSTRACT
A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound 14. Oral administration at doses ≥0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology and toxicology studies demonstrated a clean profile up to high plasma levels, thus culminating in the nomination of 14 as clinical candidate ABT-046.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Administration, Oral , Animals , Biological Availability , Caco-2 Cells , Databases, Factual , Diacylglycerol O-Acyltransferase/chemistry , Dogs , Female , Ferrets , Gastrointestinal Transit/drug effects , HeLa Cells , Hemodynamics/drug effects , Humans , Hyperlipidemias/blood , Hyperlipidemias/drug therapy , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver/metabolism , Postprandial Period , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Structure-Activity Relationship , Triglycerides/blood , Vomiting/chemically inducedABSTRACT
A new reaction of erythronolides, an intramolecular hetero-Diels-Alder, has been discovered. Heated aqueous alcoholic solutions of ABT-773 (1) and its cis isomer (3) convert slowly to cycloadducts 2 and 4, respectively. Optimal reaction conditions, mechanistic studies supported by molecular modeling, and biological activity data are reported. Single-crystal X-ray structures for both adducts 2 and 4 have been obtained.
Subject(s)
Erythromycin/analogs & derivatives , Erythromycin/chemistry , Ketolides/chemistry , Catalysis , Crystallography, X-Ray , Cyclization , Molecular Conformation , Molecular Structure , StereoisomerismABSTRACT
Functionalized erythromycin 9-oxime derivatives are 6-O-allylated under mild conditions using substituted allyl tert-butyl carbonates under palladium(0) catalysis. This allylation works well where traditional ether-forming protocols function poorly. Allyl tert-butyl carbonates provide higher yields in this reaction than lesser substituted carbonates such as ethyl or isopropyl. Aryl-substituted allyl carbonates or carbamates may be employed as well and, when used, produce trans-olefinic products.
Subject(s)
Alcohols/chemistry , Erythromycin/chemistry , AlkylationABSTRACT
A palladium catalysis-mediated approach to coupling aliphatic alcohols with allyl carbonates has been developed. The method allows for the allylation of primary, secondary, and tertiary alcohols efficiently under mild conditions. Limitations were explored as well as the asymmetric application of the chemistry. Regiochemical and olefin geometry was controlled in the coupling of unsymmetrical allylating agents. Transient allyl carbonates were observed in the coupling, which comprised the trans-carboxylation of the allyl-carbonate with the requisite alcohol.