ABSTRACT
The safety, pharmacokinetic, and pharmacodynamic effects of LY2584702, a selective inhibitor for p70 S6 serine/threonine protein kinase-1, were evaluated in healthy dyslipidemic volunteers. LY2584702 was tolerated well as a monotherapy and dose-dependently reduced low-density lipoprotein cholesterol and triglycerides by up to 60% and 50%, respectively, without significantly changing high-density lipoprotein cholesterol levels in plasma. LY2584702 also dose-dependently decreased factor V activity. Alanine aminotransferase elevations were noted in 2 subjects when LY2584702 was given with atorvastatin. We suspect that the formation of 4-aminopyrazolo[3,4-d]pyrimidine (4-APP) during metabolism may have contributed to some of the adverse effects of LY2584702, and the contribution of 4-APP to the pharmacology merits further investigation. Although clinical investigation of LY2584702 has been terminated because of hepatotoxicity risk, we suggest that a selective inhibitor of p70 S6 serine/threonine protein kinase-1 with a larger margin of safety and without the possibility of being metabolized to 4-APP may be useful in the treatment of dyslipidemia.
Subject(s)
Cholesterol, LDL/blood , Dyslipidemias/blood , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Ribosomal Protein S6 Kinases, 70-kDa/antagonists & inhibitors , Adenine/analogs & derivatives , Adenine/metabolism , Adult , Aged , Alanine Transaminase/blood , Cross-Over Studies , Female , Humans , Male , Middle Aged , Protein Kinase Inhibitors/blood , Pyrazoles/blood , Pyrimidines/blood , Single-Blind Method , Young AdultABSTRACT
LY2584702 is an inhibitor of p70 S6 kinase-1 previously developed for the treatment of cancer. In two phase 1 trials in oncology patients, significant reductions of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride were observed. In the current study, we sought to understand the potential mechanism of action of this compound in regulating lipid metabolism. In Long Evans diet-induced obese (DIO) rats, oral administration of LY2584702 for 3-4 weeks led to robust reduction of LDL-C up to 60%. An unexpected finding of liver triglyceride (TG) increase implicated a metabolite of LY2584702, 4-aminopyrazolo[3,4-day]pyrimidine (4-APP), in modulation of lipid metabolism in these rats. We showed that low-dose 4-APP, when administered orally for 3-4 weeks to Long Evans DIO rats, produced lipoprotein profile changes that were strikingly similar to LY2584702. Kinetic studies suggested that both LY2584702 and 4-APP had no effect on chylomicron-TG secretion and only exerted a modest effect on hepatic very low-density lipoprotein (VLDL)-TG secretion. In human hepatoma HepG2 cells, 4-APP, but not LY2584702, increased LDL uptake. We hypothesize that generation of the 4-APP metabolite may contribute to the efficacy of LY2584702 in lowering LDL-C in rats and potentially in humans as well. This mechanism of LDL-C lowering may include inhibition of VLDL production and increase in LDL clearance.
Subject(s)
Adenine/analogs & derivatives , Hypolipidemic Agents/pharmacology , Obesity/blood , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Adenine/pharmacology , Animals , Cholesterol, LDL/blood , Cholesterol, LDL/metabolism , Cholesterol, VLDL/biosynthesis , Cholesterol, VLDL/genetics , Gene Expression Regulation/drug effects , Hep G2 Cells , Humans , Lipid Metabolism/drug effects , Lipoproteins, LDL/metabolism , Liver/drug effects , Liver/metabolism , Male , Rats , Rats, Long-Evans , Triglycerides/metabolismABSTRACT
Potent, small molecule A beta inhibitors have been prepared that incorporate an alanine core bracketed by an N-terminal arylacetyl group and various C-terminal amino alcohols. The compounds exhibit stereospecific inhibition as demonstrated in an in vitro assay.
