Pericardial fat has been implicated in the pathogenesis of obesity-related cardiovascular disease. Whether the associations of pericardial fat and measures of cardiac structure and function are ...independent of the systemic effects of obesity and visceral adiposity has not been fully explored.
Participants from the Framingham Heart Study (n=997; 54.4% women) underwent chest and abdominal computed tomography and cardiovascular magnetic resonance imaging between 2002 and 2005. Pericardial fat, intrathoracic fat, and visceral adipose tissue quantified from multidetector computed tomography, along with body mass index and waist circumference, were examined in relation to cardiovascular magnetic resonance measures of left ventricular (LV) mass, LV end-diastolic volume, and left atrial dimension. In women, pericardial fat (r=0.20 to 0.35, P<0.001), intrathoracic fat (r=0.25 to 0.37, P<0.001), visceral adipose tissue (r=0.24 to 0.45, P<0.001), body mass index (r=0.36 to 0.53, P<0.001), and waist circumference (r=0.30 to 0.48, P<0.001) were directly correlated with LV mass, LV end-diastolic volume, and left atrial dimension. In men, pericardial fat (r=0.19 to 0.37, P<0.001), intrathoracic fat (r=0.17 to 0.31, P<0.001), visceral adipose tissue (r=0.19 to 0.36, P<0.001), body mass index (r=0.32 to 0.44, P<0.001), and waist circumference (r=0.34 to 0.44, P<0.001) were directly correlated with LV mass and left atrial dimension, but LV end-diastolic volume was not consistently associated with adiposity measures. Associations persisted after multivariable adjustment but not after additional adjustment for body weight and visceral adipose tissue, except for pericardial fat and left atrial dimension in men.
Pericardial fat is correlated with cardiovascular magnetic resonance measures, but the association is not independent of or stronger than other ectopic fat stores or proxy measures of visceral adiposity. An important exception is left atrial dimension in men. These results suggest that the systemic effects of obesity on cardiac structure and function may outweigh the local pathogenic effects of pericardial fat.
The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer’s disease drug target owing to its critical role in the production of amyloid-beta. We have previously ...reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges.
Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic ...transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment. We hypothesized that blockade of forebrain AMPA receptors without blocking cerebellar AMPA receptors would be antiepileptic and devoid of motor impairment. Taking advantage of an AMPA receptor auxiliary protein, TARP γ-8, which is selectively expressed in the forebrain and modulates the pharmacological properties of AMPA receptors, we discovered that LY3130481 selectively antagonized recombinant and native AMPA receptors containing γ-8, but not γ-2 (cerebellum) or other TARP members. Two amino acid residues unique to γ-8 determined this selectivity. We also observed antagonism of AMPA receptors expressed in hippocampal, but not cerebellar, tissue from an patient with epilepsy. Corresponding to this selective activity, LY3130481 prevented multiple seizure types in rats and mice and without motor side effects. These findings demonstrate the first rationally discovered molecule targeting specific neural circuitries for therapeutic advantage.
Display omitted
Inhibition of BACE1 has become an important strategy in the quest for disease modifying agents to slow the progression of Alzheimer’s disease. We previously reported the ...fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aβ in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 inhibitor that reached phase 2 clinical trials. Herein we describe the preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans-cyclopropyl moieties as conformational constraints. The design, details of the stereochemically complex organic synthesis, and biological activity of these BACE1 inhibitors is described.
Transmembrane AMPA receptor regulatory proteins (TARPs) are a family of scaffolding proteins that regulate AMPA receptor trafficking and function. TARP γ-8 is one member of this family and is highly ...expressed within the hippocampus relative to the cerebellum. A selective TARP γ-8-dependent AMPA receptor antagonist (TDAA) is an innovative approach to modulate AMPA receptors in specific brain regions to potentially increase the therapeutic index relative to known non-TARP-dependent AMPA antagonists. We describe here, for the first time, the discovery of a noncompetitive AMPA receptor antagonist that is dependent on the presence of TARP γ-8. Three major iteration cycles were employed to improve upon potency, CYP1A2-dependent challenges, and in vivo clearance. An optimized molecule, compound (−)-25 (LY3130481), was fully protective against pentylenetetrazole-induced convulsions in rats without the motor impairment associated with non-TARP-dependent AMPA receptor antagonists. Compound (−)-25 could be utilized to provide proof of concept for antiepileptic efficacy with reduced motor side effects in patients.
6-(1S)-1-1-5-(2-hydroxyethoxy)-2-pyridylpyrazol-3-ylethyl-3H-1,3-benzothiazol-2-one (LY3130481 or CERC-611) is a selective antagonist of AMPA receptors containing transmembrane AMPA receptor ...regulatory protein (TARP) γ−8. This molecule has been characterized as a potent and efficacious anticonvulsant in an array of acute and chronic epilepsy models in rodents. The present set of experiments was designed to assess the effects of LY3130481 on the electroencephelogram (EEG), cognitive function, and neurochemical outflow. LY3130481 disrupted food-maintained responding in rats and spontaneous alternation in a Y-maze in mice. In rat fear conditioning, LY3130481 caused a deficit in trace (hippocampal-dependent), but not in delay fear conditioning. Although these effects on cognitive performances were observed, the known cognitive-impairing anticonvulsant, topiramate, did not always produce deficits under these assay conditions. LY3130481 produced modest increases in wake times in rats. In addition, LY3130481 was able to attenuate some impairing effects of standard antiepileptic drugs. The motor-impairing effects of the lacosamide were attenuated by LY3130481 as was the decrease in non-rapid-eye movement sleep induced by carbamazepine. Evaluation of the effect of LY3130481 on neurotransmitter and metabolite efflux in the rat medial prefrontal cortex, using in vivo microdialysis, revealed significant increases in the pro-cognitive and wake-promoting neurotransmitters, histamine and acetylcholine, as well as in serotonin, telemethylhistamine, 5-HIAA, HVA and MHPG. LY3130481 thus presents a novel behavioral profile that will have to be evaluated in patients to fully appreciate its implications for therapeutics. LY3130481 is currently under clinical development as CERC-611 as an antiepileptic.
•LY3130481 (CERC-611) is a selective antagonist of AMPA receptors TARP γ−8 protein.•LY3130481 is currently under clinical development as CERC-611 as an antiepileptic.•LY3130481 produced mixed results in rodent cognition assessments.•LY3130481 produced modest increases in wake times in rats and increased wake and cognition-associated neurotransmitters.•LY3130481 attenuated some impairing effects of standard antiepileptic drugs.
6-(1S)-1-1-5-(2-hydroxyethoxy)-2-pyridylpyrazol-3-ylethyl- 3H-1,3-benzothiazol-2-one (LY3130481 or CERC-611) is a selective antagonist of AMPA receptors containing transmembrane AMPA receptor ...regulatory protein (TARP) γ-8 that is under development for epilepsy. The present study provided a broad inquiry into its anticonvulsant properties. LY3130481 was anticonvulsant in multiple acute seizure provocation models in mice and rats. In addition, LY3130481 was effective against absence seizures in the GAERS genetic model and in the Frings mouse model. Likewise, LY3130481 attenuated convulsions in mice and rats with long-term induction of seizures (e.g., corneal, pentylenetetrazole, hippocampal, and amygdala kindled seizures). In slices of epileptic human cortex, LY3130481 significantly decreased neuronal firing frequencies. LY3130481 displaced from rat brain a radioligand specific for AMPA receptors associated with TARP γ-8 whereas non-TARP-selective molecules did not. Binding was also observed in hippocampus freshly transected from a patient.
Taken as a whole, the findings reported here establish the broad anticonvulsant efficacy of LY3130481 indicating that blockade of AMPA receptors associated with TARP γ-8 is sufficient for these protective effects.
Selective inhibitors of the glycine transporter 1 (GlyT1) have been implicated in central nervous system disorders related to hypoglutamatergic function such as schizophrenia. The selective GlyT1 ...inhibitors ALX5407 (NFPS) and LY2365109 {2-(4-benzo1,3dioxol-5-yl-2-
tert-butylphenoxy)ethyl-methylamino}-acetic acid increased cerebrospinal fluid levels of glycine and potentiated NMDA-induced increases in dialysate levels of neurotransmitters in the prefrontal cortex (PFC) and the striatum. However, higher doses produced both stimulatory and inhibitory effects on motor performance and impaired respiration, suggesting significant involvement of cerebellar and brain stem areas. A dual probe microdialysis study showed that ALX5407 transiently elevated extracellular levels of glycine in the PFC with more sustained increases in the cerebellum. In support of these findings, immuno-staining with pan-GlyT1 and GlyT1a antibodies showed a higher abundance of immunoreactivity in the brain stem/cerebellum as compared to the frontal cortical/hippocampal brain areas in four different species studied, including the mouse, rat, monkey and human. In addition, the inhibitory effects of ALX5407 on cerebellar levels of cGMP in the mouse could be reversed by the glycine A receptor antagonist strychnine but not the glycine B receptor antagonist L-701324. We propose that the adverse events seen with higher doses of ALX5407 and LY2365109 are the result of high GlyT1 inhibitory activity in caudal areas of the brain with sustained elevations of extracellular glycine. High levels of glycine in these brain areas may result in activation of strychnine-sensitive glycine A receptors that are inhibitory on both motor activity and critical brain stem functions such as respiration.
A large body of literature has reported differences in exposure to environments supporting either healthy (e.g. supermarkets) or unhealthy (e.g. fast food outlets) dietary choices by neighborhood ...characteristics. We explored the associations of both supermarkets and fast food outlets availability with neighborhood characteristics, and clustering of these two outlet types in a largely rural state. Compared to block groups without a supermarket, those with a supermarket had a significantly higher income, higher housing value, larger population with high school education and above, lower minority population and lower population living below poverty even after controlling for urbanicity and population density of census block groups. Surprisingly, a similar relationship was found for block groups with and without fast food outlets. This was due to spatial co-occurrence and clustering of fast food outlets around supermarket locations. Hence, future studies exploring the associations of food environment with diet or diet-related health outcome should concurrently examine all aspects of food environment (healthy and unhealthy).
•Block groups with supermarkets had a significantly higher SES than without supermarket.•Similar relationship was observed for block groups with or without fast food outlets.•Similar patterning of the supermarkets and fast food outlets by neighborhood characteristics.•Spatial co-occurrence of supermarkets and fast food outlets in geographic space.
PDF
