piperidines and Hypertriglyceridemia

Actionable mutations are tested as standard of care for all new metastatic non-small cell lung cancers. Tumors harboring an anaplastic lymphoma kinase mutation respond to tyrosine kinase inhibitors targeting anaplastic lymphoma kinase pathway. Patients are monitored for common adverse effects, although we occasionally encounter unexpected side effects.. Prior to starting alectinib, our patient's triglyceride level was 420 mg/dL. While he consumed alcohol, he had no other traditional risk factor. To our knowledge, this is the first reported case of hypertriglyceridemia-induced acute pancreatitis related to treatment with an anaplastic lymphoma kinase inhibitor.

Topics: Acute Disease; Adenocarcinoma; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biopsy; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Hypertriglyceridemia; Lung Neoplasms; Male; Middle Aged; Pancreatitis; Piperidines; Protein Kinase Inhibitors

We investigated the association between retinol-binding protein 4 (RBP(4)) and apolipoprotein B (ApoB)-containing lipoproteins. Obese or overweight, hypertriglyceridemic patients underwent the following interventions for 3 months: (1) Diet (n = 20), (2) Diet + fenofibrate (n = 18), (3) Diet + rimonabant (n = 8). Circulating RBP4 decreased during dietary treatment. The percentage change in RBP(4) was positively correlated with the percentage changes in very-low density lipoprotein cholesterol (r = .570, P = .02), low-density lipoprotein cholesterol ([LDL-C]; r = .605, P = .01), ApoB (r = .705, P = .007), and small dense LDL-C ([sdLDL-C]; r = .872, P < .001). The percentage change in RBP4 was the best predictor of the percentage changes in sdLDL-C and ApoB. Rimonabant treatment reduced RBP4, whereas fenofibrate increased RBP4 during the first month of therapy followed by a subsequent decrease. In conclusion, RBP4 may significantly influence the metabolic pathways responsible for changes in ApoB lipoprotein subspecies, thus RBP4 may be associated with cardiovascular disease risk.

Topics: Adult; Apolipoproteins B; Caloric Restriction; Diet, Fat-Restricted; Female; Fenofibrate; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Retinol-Binding Proteins, Plasma; Rimonabant

Herein we describe the discovery and characterization of a novel, piperidine-based inhibitor of cholesteryl ester transfer protein (CETP) with a core structure distinct from other reported CETP inhibitors. A versatile synthesis starting from 4-methoxypyridine enabled an efficient exploration of the SAR, giving a lead molecule with potent CETP inhibition in human plasma. The subsequent optimization focused on improvement of pharmacokinetics and mitigation of off-target liabilities, such as CYP inhibition, whose improvement correlated with increased lipophilic efficiency. The effort led to the identification of an achiral, carboxylic acid-bearing compound 16 (TAP311) with excellent pharmacokinetics in rats and robust efficacy in hamsters. Compared to anacetrapib, the compound showed substantially reduced lipophilicity, had only modest distribution into adipose tissue, and retained potency in hypertriglyceridemic plasma in vitro and in vivo. Furthermore, in contrast to torcetrapib, the compound did not increase aldosterone secretion in human adrenocortical carcinoma cells nor in chronically cannulated rats. On the basis of its preclinical efficacy and safety profile, the compound was advanced into clinical trials.

Topics: Aged; Animals; Chick Embryo; Cholesterol Ester Transfer Proteins; Humans; Hypertriglyceridemia; Male; Mesocricetus; Piperidines; Rats; Structure-Activity Relationship

Diverse serine hydrolases including endocannabinoid metabolizing enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have been suggested as secondary targets for organophosphate (OP) agents to exert adverse toxic effects such as lipid homeostasis disruption. The goal of this investigation is to verify that a major OP insecticide fenitrothion (FNT) induces plasma hypertriglyceridemia through the inhibition of FAAH and/or MAGL in comparison with that elicited by isopropyl dodecylfluorophosphonate (IDFP), a potent FAAH/MAGL inhibitor. Fasted mice were treated intraperitoneally with FNT or IDFP and were subsequently sacrificed for evaluations of plasma triglyceride (TG) levels and liver FAAH/MAGL activities. Plasma TG levels were significantly enhanced by the FNT or IDFP treatment (1.7- or 4.8-fold, respectively) compared with that of vehicle control. The IDFP exposure reduced the liver FAAH and MAGL activities, whereas the FNT exposure led to the preferential FAAH inhibition. The brain acetylcholinesterase was almost unaffected by the FNT or IDFP treatment, thus leading to no neurotoxic sign. Intriguingly, the TG elevations were averted by concomitant administration with the cannabinoid receptor antagonist AM251. The present findings suggest that OP agents induce plasma hypertriglyceridemia in mouse through single or dual inhibition of FAAH or/and MAGL, apparently leading to overstimulation of cannabinoid signal regulating energy metabolism.

Topics: Acetylcholinesterase; Amidohydrolases; Animals; Biomarkers; Brain; Cannabinoid Receptor Antagonists; Dose-Response Relationship, Drug; Endocannabinoids; Enzyme Inhibitors; Fenitrothion; GPI-Linked Proteins; Hydrolysis; Hypertriglyceridemia; Insecticides; Liver; Male; Mice; Mice, Inbred ICR; Monoacylglycerol Lipases; Piperidines; Pyrazoles; Receptors, Cannabinoid; Triglycerides; Up-Regulation

Piperidine-based peroxisome proliferator-activated receptor-α agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus. Four-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3 mg/kg per day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria, and urinary excretion of 8-epi PGF(2α), a product of the nonenzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF(2α) excretion, and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy, and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF(2α), possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy.

Topics: Albuminuria; Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Disease Progression; Female; Glomerular Mesangium; Hypercholesterolemia; Hypertriglyceridemia; Hypertrophy; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Kidney; Mice; Mice, Inbred Strains; Mice, Obese; Obesity; Piperidines; PPAR alpha; Propionates

In the present paper, the age-related changes in the vasoconstrictive endothelin-mediated response to insulin in aortas of normal and hypertensive, hypertriglyceridemic, hyperinsulinemic (HTG) rats were studied. To develop HTG rats, weanling male Wistar animals were given 30% sucrose in their drinking water for 4, 6, 12 and 18 months. Blood pressure was increased in HTG rats for up to 12 months showing a maximum at 6 months (138.9+/-0.8 mmHg). In vitro contractions were elicited with 40 mM KCl in the presence and absence 50 microU/ml insulin and of endothelin-receptor antagonists BQ123 and BQ788. Tension development to KCl was not modified during aging in control rats but was increased at 4 and 6 months in HTG rats. Increased endothelin release induced by insulin remained constant in normal rats, while in HTG rats it was higher than in controls at all ages. ET(A) blocker participation alone increased during aging in control rats while both receptor blockers participated in HTG rats. Our results suggest that the vasoconstrictive capacity to KCl plus insulin decreases during aging and that this decrease is greater in HTG rats. The participation of endothelin receptors in the aging process differs in control and HTG rats.

Topics: Aging; Animals; Antihypertensive Agents; Aorta; Blood Glucose; Blood Pressure; Endothelin Receptor Antagonists; Endothelins; Hypertension; Hypertriglyceridemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Potassium Chloride; Rats; Rats, Wistar; Triglycerides; Vasoconstriction; Weight Loss

New fibrates containing piperidine, 4-hydroxypiperidine, piperidin-3-ene, and piperazine moieties in the structures were synthesized and evaluated. Among the synthesized compounds, 2-[3-[1-(4-fluorobenzoyl)-piperidin-4yl]phenoxyl-2-methylpropanoic acid (9aA: AHL-157) showed very superior activities in decreasing triglyceride, cholesterol, and blood sugar compared to bezafibrate in mice and rats.

Topics: Animals; Disease Models, Animal; Hypercholesterolemia; Hypertriglyceridemia; Hypoglycemic Agents; Hypolipidemic Agents; Male; Mice; Mice, Inbred ICR; Piperazine; Piperazines; Piperidines; Propionates; Rats; Rats, Sprague-Dawley

Insulin-elicited endothelin release in hypertriglyceridemic, hypertensive, hyperinsulinemic (HTG) rats was shown. Weanling male Wistar rats were given 30% sucrose in their drinking water for 20-24 wk. In vitro contractions of aorta and femoral arteries were elicited with 40 mM KCl. Endothelin release induced with KCl plus 50 microU/ml insulin resulted in increases in contractile responses: 41 +/- 5.9 and 57 +/- 6% for control and 65.5 +/- 6 and 95 +/- 9% for HTG aortas and femoral arteries, respectively. The endothelin ET(B)-receptor blocker BQ-788 decreased responses to KCl + insulin by 39 +/- 8 and 53 +/- 5% in control and 48 +/- 13 and 79 +/- 3.5% in HTG aortas and femoral arteries, respectively. The ET(A)-receptor antagonist PD-151242 inhibited these responses by 12 +/- 10 and 1 +/- 9% in control and by 51.5 +/- 9 and 58.5 +/- 1% in HTG aortas and femoral arteries, respectively. These results suggest that endothelin may contribute to the hypertension in this model.

Topics: Animals; Animals, Newborn; Antihypertensive Agents; Azepines; Endothelin-1; Glucose Tolerance Test; Hypertension; Hypertriglyceridemia; Insulin; Male; Muscle Contraction; Muscle, Smooth, Vascular; Oligopeptides; Piperidines; Potassium Chloride; Rats; Rats, Wistar

Topics: Anticholesteremic Agents; Contraindications; Estrogen Antagonists; Estrogen Replacement Therapy; Estrogens; Female; Humans; Hyperlipidemia, Familial Combined; Hypertriglyceridemia; Lipoproteins, HDL; Lipoproteins, LDL; Liver; Piperidines; Raloxifene Hydrochloride; Tamoxifen