ABSTRACT
This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.
Subject(s)
Acetyl-CoA Carboxylase/antagonists & inhibitors , Benzimidazoles/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Indazoles/chemical synthesis , Indoles/chemical synthesis , Pyrazoles/chemical synthesis , Spiro Compounds/chemical synthesis , Animals , Benzimidazoles/chemistry , Drug Design , Humans , Hypoglycemic Agents/chemistry , Indazoles/chemistry , Indoles/chemistry , Isoenzymes/antagonists & inhibitors , Liver/enzymology , Muscle, Skeletal/enzymology , Pyrazoles/chemistry , Quantitative Structure-Activity Relationship , Rats , Spiro Compounds/chemistryABSTRACT
Focused SAR studies were carried out around 5-heteroaryl and 1-amide portions of the 2-chlorobenzamide scaffold, resulting in the discovery of a potent, metabolically stable and centrally penetrable antagonist against P2X(7) receptor.
Subject(s)
Anti-Inflammatory Agents/chemistry , Benzamides/chemistry , Purinergic P2 Receptor Antagonists , Pyrimidines/chemistry , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacokinetics , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , Central Nervous System/drug effects , Drug Discovery , Humans , Male , Microsomes, Liver/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2X7 , Structure-Activity RelationshipABSTRACT
The intracellular distribution of fluorescent-labeled polyamides was examined in live cells. We showed that BODIPY-labeled polyamides accumulate in acidic vesicles, mainly lysosomes, in the cytoplasm of HCT116 colon cancer cells and human rheumatoid synovial fibroblasts (RSF). Verapamil blocked vesicular accumulation and led to nuclear accumulation of the BODIPY-labeled polyamide in RSFs. We infer that the basic amine group commonly found at the end of synthetic polyamide chains is responsible for their accumulation in cytoplasmic vesicles in mammalian cells. Modifying the charge on a polyamide by replacing the BODIPY moiety with a fluorescein moiety on the amine tail allowed the polyamide to localize in the nucleus of the cell and bypass the cytoplasmic vesicles in HCT116 cells.
