James R. Tata

Niacin Lipid Efficacy Is Independent of Both the Niacin Receptor GPR109A and Free Fatty Acid Suppression

GPR109A is not the target mediating niacin’s lipid efficacy and the free fatty acid hypothesis does not explain niacin’s mechanism of action. Breaking Free of the “FFA Hypothesis” Free fatty acids (FFAs) appear in the blood plasma after a meal. Niacin—a vitamin that helps to regulate lipid levels in the body—is given to patients to reduce the amount of FFAs. It also works to raise “good” cholesterol [high-density lipoprotein (HDL)] and lower both “bad” cholesterol [low-density lipoprotein (LDL)] and triglycerides. The “FFA hypothesis” suggests that niacin works to exert these beneficial lipid effects by limiting the amount of FFAs available to synthesize triglycerides. Lauring, Taggart, and colleagues now challenge this long-standing theory. In studies in mice and humans, the authors debunk the hypothesis, showing that the effect on HDL, LDL, and triglycerides is not directly linked to FFAs. To study the lipid-modifying effects of niacin (nicotinic acid), Lauring et al. used a genetic, humanized mouse model lacking the LDL receptor. In these animals, niacin increased HDL cholesterol levels, as expected. Lack of GPR109A in these animals blocked the anti-lipolytic effect of nicotinic acid on FFAs but had no effect on drug-related changes in plasma HDL and LDL cholesterol or triglyceride levels. Treatment of the mice with a GPR109A agonist, MK-1903, also caused an anti-lipolytic effect but did not affect levels of triglyceride or LDL and HDL cholesterol. Together, these in vivo preclinical studies suggest that niacin works to lower FFAs through GPR109A but has an independent mechanism of action on other lipids. The authors addressed the role of GPR109A in humans by testing the effects of MK-1903 and of another synthetic GPR109A agonist in clinical trials. Both agonists affected FFA lipolysis but had only minor effects on HDL cholesterol and triglyceride levels in patients, thus mirroring results seen in animals and showing that niacin works independently of GPR109A to modify dyslipidemia. The studies by Lauring et al. point to a new, yet-uncovered mechanism of action for niacin’s beneficial effects on lipids in the blood. Despite overturning the FFA hypothesis and potentially redirecting drug development away from GPR109A agonists, niacin could still be useful for treating other diseases in patients, including atherosclerosis and inflammation, where GPR109A plays a major role in cell signaling. Nicotinic acid (niacin) induces beneficial changes in serum lipoproteins and has been associated with beneficial cardiovascular effects. Niacin reduces low-density lipoprotein, increases high-density lipoprotein, and decreases triglycerides. It is well established that activation of the seven-transmembrane Gi-coupled receptor GPR109A on Langerhans cells results in release of prostaglandin D2, which mediates the well-known flushing side effect of niacin. Niacin activation of GPR109A on adipocytes also mediates the transient reduction of plasma free fatty acid (FFA) levels characteristic of niacin, which has been long hypothesized to be the mechanism underlying the changes in the serum lipid profile. We tested this “FFA hypothesis” and the hypothesis that niacin lipid efficacy is mediated via GPR109A by dosing mice lacking GPR109A with niacin and testing two novel, full GPR109A agonists, MK-1903 and SCH900271, in three human clinical trials. In mice, the absence of GPR109A had no effect on niacin’s lipid efficacy despite complete abrogation of the anti-lipolytic effect. Both MK-1903 and SCH900271 lowered FFAs acutely in humans; however, neither had the expected effects on serum lipids. Chronic FFA suppression was not sustainable via GPR109A agonism with niacin, MK-1903, or SCH900271. We conclude that the GPR109A receptor does not mediate niacin’s lipid efficacy, challenging the long-standing FFA hypothesis.

3-(1H-Tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (MK-0354): A Partial Agonist of the Nicotinic Acid Receptor, G-Protein Coupled Receptor 109a, with Antilipolytic but No Vasodilatory Activity in Mice

The discovery and profiling of 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (5a, MK-0354), a partial agonist of GPR109a, is described. Compound 5a retained the plasma free fatty acid lowering effects in mice associated with GPR109a agonism, but did not induce vasodilation at the maximum feasible dose. Moreover, preadministration of 5a blocked the flushing effect induced by nicotinic acid but not that induced by PGD2. This profile made 5a a suitable candidate for further study for the treatment of dyslipidemia.

Discovery of a novel glucagon receptor antagonist N-[(4-{(1S)-1-[3-(3, 5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the treatment of type II diabetes.

A potent, selective glucagon receptor antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC(50) of 6.6 nM) and functional cAMP activity (IC(50) of 15.7 nM). It is selective for glucagon receptor relative to other family B GPCRs, showing IC(50) values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.

Effects of a niacin receptor partial agonist, MK-0354, on plasma free fatty acids, lipids, and cutaneous flushing in humans

BACKGROUND Development of niacin-like agents that favorably affect lipids with an improved flushing profile would be beneficial. OBJECTIVE To evaluate a niacin receptor partial agonist, MK-0354, in Phase I and II studies. METHODS The pharmacokinetic/pharmacodynamic effects of single and multiple doses (7 days) of MK-0354 (300-4000 mg) were evaluated in two Phase I studies conducted in healthy men. A Phase II study assessed the effects of MK-0354 2.5 g once daily on lipids during 4 weeks in 66 dyslipidemic patients. RESULTS MK-0354 single doses up to 4000 mg and multiple doses (7 days) up to 3600 mg produced robust dose-related reductions in free fatty acid (FFA) over 5 hours. Single doses of MK-0354 300 mg and extended release-niacin (Niaspan) 1 g produced comparable reductions in FFA. Suppression of FFA following 7 daily doses of MK-0354 was similar to that after a single dose. In the Phase II study, MK-0354 2.5 g produced little flushing but no clinically meaningful effects on lipids (placebo-adjusted percent change: high-density lipoprotein cholesterol, 0.4%, 95% confidence interval -5.2 to 6.0; low-density lipoprotein cholesterol, -9.8%, 95% confidence interval -16.8 to -2.7; triglyceride, -5.8%, 95% confidence interval -22.6 to 11.9). CONCLUSION Treatment with MK-0354 for 7 days resulted in plasma FFA suppression with minimal cutaneous flushing. However, 4 weeks of treatment with MK-0354 failed to produce changes in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, or triglycerides.

Discovery of spirocyclic secondary amine-derived tertiary ureas as highly potent, selective and bioavailable soluble epoxide hydrolase inhibitors.

Spirocyclic secondary amine-derived trisubstituted ureas were identified as highly potent, bioavailable and selective soluble epoxide hydrolase (sEH) inhibitors. Despite good oral exposure and excellent ex vivo target engagement in blood, one such compound, rac-1a, failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This study posed the question as to whether sEH inhibition provides a robust mechanism leading to a significant antihypertensive effect.

Discovery of novel, potent, selective, and orally active human glucagon receptor antagonists containing a pyrazole core.

A novel class of 1,3,5-pyrazoles has been discovered as potent human glucagon receptor antagonists. Notably, compound 26 is orally bioavailable in several preclinical species and shows selectivity towards cardiac ion channels, other family B receptors such hGIP and hGLP1, and a large panel of enzymes and additional receptors. When dosed orally, compound 26 is efficacious in suppressing glucagon induced plasma glucose excursion in rhesus monkey and transgenic murine pharmacodynamic models at 1 and 10 mpk, respectively.

Discovery of a Highly Potent, Selective, and Bioavailable Soluble Epoxide Hydrolase Inhibitor with Excellent Ex Vivo Target Engagement

4-Substituted piperidine-derived trisubstituted ureas are reported as highly potent and selective inhibitors for sEH. The SAR outlines approaches to improve activity against sEH and reduce ion channel and CYP liability. With minimal off-target activity and a good PK profile, the benchmark 2d exhibited remarkable in vitro and ex vivo target engagement. The eutomer entA-2d also elicited vasodilation effect in rat mesenteric artery.

Discovery of potent, orally active benzimidazole glucagon receptor antagonists.

The discovery and optimization of potent and selective aminobenzimidazole glucagon receptor antagonists are described. One compound possessing moderate pharmacokinetic properties in multiple preclinical species was orally efficacious at inhibiting glucagon-mediated glucose excursion in transgenic mice expressing the human glucagon receptor, and in rhesus monkeys. The compound also significantly lowered glucose levels in a murine model of diabetes.

Discovery of a Biaryl Cyclohexene Carboxylic Acid (MK-6892): A Potent and Selective High Affinity Niacin Receptor Full Agonist with Reduced Flushing Profiles in Animals as a Preclinical Candidate

Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.

(1aR,5aR)1a,3,5,5a-Tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (MK-1903): a potent GPR109a agonist that lowers free fatty acids in humans.

G-protein coupled receptor (GPCR) GPR109a is a molecular target for nicotinic acid and is expressed in adipocytes, spleen, and immune cells. Nicotinic acid has long been used for the treatment of dyslipidemia due to its capacity to positively affect serum lipids to a greater extent than other currently marketed drugs. We report a series of tricyclic pyrazole carboxylic acids that are potent and selective agonists of GPR109a. Compound R,R-19a (MK-1903) was advanced through preclinical studies, was well tolerated, and presented no apparent safety concerns. Compound R,R-19a was advanced into a phase 1 clinical trial and produced a robust decrease in plasma free fatty acids. On the basis of these results, R,R-19a was evaluated in a phase 2 study in humans. Because R,R-19a produced only a weak effect on serum lipids as compared with niacin, we conclude that the beneficial effects of niacin are most likely the result of an undefined GPR109a independent pathway.