ABSTRACT
Activation of pyruvate dehydrogenase (PDH) by inhibition of pyruvate dehydrogenase kinase (PDHK) has the potential for the treatment of diabetes mellitus and its complications, caused by the malfunction of the glycolytic system and glucose oxidation. In this paper, we describe the identification of novel PDHK inhibitors with a fluorene structure. High-throughput screening using our in-house library provided compound 6 as a weak inhibitor that occupied the allosteric lipoyl group binding site in PDHK2. Structure-based drug design (SBDD) while addressing physicochemical properties succeeded in boosting inhibitory activity approximately 700-fold. Thus obtained compound 32 showed favorable pharmacokinetics profiles supported by high membrane permeability and metabolic stability, and exhibited activation of PDH in rat livers and a glucose lowering effect in Zucker fatty rats.
Subject(s)
Drug Design , Fluorenes , Protein Kinase Inhibitors , Protein Serine-Threonine Kinases , Pyruvate Dehydrogenase Acetyl-Transferring Kinase , Rats, Zucker , Animals , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/antagonists & inhibitors , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism , Rats , Fluorenes/chemistry , Fluorenes/chemical synthesis , Fluorenes/pharmacology , Structure-Activity Relationship , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Molecular Structure , Humans , Dose-Response Relationship, DrugABSTRACT
AIM: Leukocyte profile has been related to clinical outcome in patients with ST-segment elevation (STE) myocardial infarction (MI). However, whether eosinophil to leukocyte ratio (ELR) predicts clinical outcome in patients who have undergone primary percutaneous coronary intervention (PCI) remains unclear. Therefore, we examined the prognostic value of ELR in this patient population. METHODS: We retrospectively analyzed the data of 331 consecutive patients who underwent primary PCI for STEMI between January 2009 and March 2015. All leukocyte types were counted and ELR was calculated for all patients 24 h after hospital admission. The primary study endpoint was major adverse cardiac events (MACEs) within up to one year of follow-up duration. RESULTS: MACEs including cardiac deaths in 9.4% of the patients, MI in 1.5%, and target lesion or vessel revascularization in 10.3%, occurred within one year in 68 patients (20.5%). The mean ELR was significantly lower in patients with MACEs than in patients without MACEs (0.20±0.51 vs.0.49±0.66, respectively; pï¼0.001). An ELR ï¼0.1 at 24 h was identified as the best cut-off value for mortality prediction. Multivariate analysis identified that an ELR ï¼0.1 (odds ratio [OR]=0.38; 95% confidence interval [CI]=0.22-0.67; pï¼0.001) and chronic kidney disease (OR=2.38; CI=1.33-4.24; p=0.003) are independent predictors of MACEs. CONCLUSION: In primary PCI patients with STEMI, ELR at 24 h was an independent predictor of MACEs in addition to the usual coronary risk factors and commonly used biomarkers.
