Lung-to-Heart Nano-in-Micro Peptide Promotes Cardiac Recovery in a Pig Model of Chronic Heart Failure.

Background: The lack of disease-modifying drugs is one of the major unmet needs in patients with heart failure (HF). Peptides are highly selective molecules with the potential to act directly on cardiomyocytes. However, a strategy for effective delivery of therapeutics to the heart is lacking.

High Glucose Activates YAP Signaling to Promote Vascular Inflammation.

Background And Aims: The YAP/TAZ signaling is known to regulate endothelial activation and vascular inflammation in response to shear stress. Moreover, YAP/TAZ signaling plays a role in the progression of cancers and renal damage associated with diabetes. However, whether YAP/TAZ signaling is also implicated in diabetes-associated vascular complications is not known.

Apelin improves cardiac function mainly through peripheral vasodilation in a mouse model of dilated cardiomyopathy.

There is growing evidence that apelin plays a role in the regulation of the cardiovascular system by increasing myocardial contractility and acting as a vasodilator. However, it remains unclear whether apelin improves cardiac contractility in a load-dependent or independent manner in pathological conditions. For this purpose we investigated the cardiovascular effects of apelin in α-actin transgenic mice (mActin-Tg mice), a model of cardiomyopathy.

Lipoprotein(a) Cellular Uptake Ex Vivo and Hepatic Capture In Vivo Is Insensitive to PCSK9 Inhibition With Alirocumab.

Lipoprotein(a) (Lp[a]) is the most common genetically inherited risk factor for cardiovascular disease. Many aspects of Lp(a) metabolism remain unknown. We assessed the uptake of fluorescent Lp(a) in primary human lymphocytes as well as Lp(a) hepatic capture in a mouse model in which endogenous hepatocytes have been ablated and replaced with human ones.

Lysophosphatidic Acid Receptor Agonism: Discovery of Potent Nonlipid Benzofuran Ethanolamine Structures.

Lysophosphatidic acid (LPA) is the natural ligand for two phylogenetically distinct families of receptors (LPA LPA) whose pathways control a variety of physiologic and pathophysiological responses. Identifying the benefit of balanced activation/repression of LPA receptors has always been a challenge because of the high lability of LPA and the limited availability of selective and/or stable agonists. In this study, we document the discovery of small benzofuran ethanolamine derivatives (called CpX and CpY) behaving as LPA agonists.

Exploring the fate of inhaled monoclonal antibody in the lung parenchyma by microdialysis.

Therapeutic antibodies (Abs) are emerging as major drugs to treat respiratory diseases, and inhalation may provide substantial benefits for their delivery. Understanding the behavior of Abs after pulmonary deposition is critical for their development. We investigated the pharmacokinetics of a nebulized Ab by continuous sampling in lung parenchyma using microdialysis in non-human primates.

PCSK9 inhibition with alirocumab reduces lipoprotein(a) levels in nonhuman primates by lowering apolipoprotein(a) production rate.

Therapeutic antibodies targeting proprotein convertase subtilisin kexin type 9 (PCSK9) (e.g. alirocumab) lower low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] levels in clinical trials.

The complexity of lipoprotein (a) lowering by PCSK9 monoclonal antibodies.

Since 2012, clinical trials dedicated to proprotein convertase subtilisin kexin type 9 (PCSK9) inhibition with monoclonal antibodies (mAbs) have unambiguously demonstrated robust reductions not only in low-density lipoprotein (LDL) cholesterol (LDL-C) but also in lipoprotein (a) [Lp(a)] levels. The scientific literature published prior to those studies did not provide any evidence for a link between PCSK9 and Lp(a) metabolism. More recent investigations, either in vitro or in vivo, have attempted to unravel the mechanism(s) by which PCSK9 mAbs reduce circulating Lp(a) levels, with some showing a specific implication of the LDL receptor (LDLR) in Lp(a) clearance whereas others found no significant role for the LDLR in that process.

PCSK9 Modulates the Secretion But Not the Cellular Uptake of Lipoprotein(a) Ex Vivo: An Effect Blunted by Alirocumab.

To elucidate how the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor alirocumab modulates lipoprotein(a) [Lp(a)] plasma levels, the authors performed a series of Lp(a) uptake studies in primary human hepatocytes and dermal fibroblasts and measured Lp(a) secretion from human hepatocytes. They found that Lp(a) cellular uptake occurred in a low-density lipoprotein receptor-independent manner. Neither PCSK9 nor alirocumab altered Lp(a) internalization.

Synthesis and multiparametric evaluation of thiadiazoles and oxadiazoles as diacylglycerol acyltransferase type 1 inhibitors.

Chemical modulation of a formerly disclosed DGAT-1 inhibitor resulted in the identification of a compound with a suitable profile for preclinical development. Optimisation of solubility is discussed and a PK/PD study is presented.

Synthesis, characterization, and biological assessment of the four stereoisomers of the H(3) receptor antagonist 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3']bipyrrolidinyl-1'-yl)phenyl]benzamide.

This Letter describes the asymmetric synthesis of the four stereoisomers (8a-8d) of a potent and highly selective histamine H3 receptor (H3R) antagonist, 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3']bipyrrolidinyl-1'-yl) phenyl]benzamide (1). The physico-chemical properties, in vitro H3R affinities and ADME of 8a-8d were determined. Stereoisomer 8c (2S,3'S) displayed superior in vitro H3R affinity over other three stereoisomers and was selected for further profiling in in vivo PK and drug safety.

Discovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (part II).

A novel series of histamine H3 receptor (H3R) antagonists was derived from an arylurea lead series (1) via bioisosteric replacement of the urea functionality by an amide linkage. The arylamide series was optimized through SAR studies by a broad variation of substituents in the left-hand side benzoyl residue (analogs 2a-2ag) or replacement of the benzoyl moiety by heteroarylcarbonyl residues (analogs 5a-5n). Compounds 2p and 2q were identified within the series as potent and selective H3R antagonists/inverse agonists with acceptable overall profile.

Discovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (part I).

A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays.

Discovery of SAR184841, a potent and long-lasting inhibitor of 11β-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D.

Starting from 11β-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11β-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes.

Fasting induces CART down-regulation in the zebrafish nervous system in a cannabinoid receptor 1-dependent manner.

Central and peripheral mechanisms modulate food intake and energy balance in mammals and the precise role of the type 1 cannabinoid receptor (CB1) in these processes is still being explored. Using the zebrafish, Danio rerio, we show that rimonabant, a CB1-specific antagonist with an EC(50) of 5.15 × 10(-8) m, decreases embryonic yolk sac reserve use.

SAR110894, a potent histamine H₃-receptor antagonist, displays procognitive effects in rodents.

SAR110894 is a novel histamine H₃-R ligand, displaying high and selective affinity for human, rat or mouse H₃-Rs. SAR110894 is a potent H₃-R antagonist at native receptors, reversing R-α-methylhistamine-induced inhibition of electrical field stimulation contraction in the guinea-pig ileum. Additionally, SAR110894 inhibited constitutive GTPγS binding at human H₃-Rs demonstrating inverse agonist properties.

Thiadiazoles as new inhibitors of diacylglycerol acyltransferase type 1.

A novel class of DGAT1 inhibitors containing a thiadiazole core has been discovered. Chemical optimization lead to inhibitors of human DGAT1 with an appropriate ADME profile and that show in vivo activity in target tissues.

The central cannabinoid CB1 receptor is required for diet-induced obesity and rimonabant's antiobesity effects in mice.

Cannabinoid receptor CB1 is expressed abundantly in the brain and presumably in the peripheral tissues responsible for energy metabolism. It is unclear if the antiobesity effects of rimonabant, a CB1 antagonist, are mediated through the central or the peripheral CB1 receptors. To address this question, we generated transgenic mice with central nervous system (CNS)-specific knockdown (KD) of CB1, by expressing an artificial microRNA (AMIR) under the control of the neuronal Thy1.

Beneficial effect of a chronic treatment with rimonabant on pancreatic function and beta-cell morphology in Zucker Fatty rats.

Recent studies suggested the involvement of the endocannabinoid pathway on insulin secretion in RINm5F cells or rat islets. Animal and clinical studies have reported beneficial effects of the selective cannabinoid 1 receptor antagonist rimonabant on glucose homeostasis. The aim of this study was to investigate the in vivo effects of rimonabant on pancreatic function in Zucker Fatty rats.

Adiponectin is required to mediate rimonabant-induced improvement of insulin sensitivity but not body weight loss in diet-induced obese mice.

The increase in adiponectin levels in obese patients with untreated dyslipidemia and its mRNA expression in adipose tissue of obese animals are one of the most interesting consequences of rimonabant treatment. Thus, part of rimonabant's metabolic effects could be related to an enhancement of adiponectin secretion and its consequence on the modulation of insulin action, as well as energy homeostasis. The present study investigated the effects of rimonabant in adiponectin knockout mice (Ad(-/-)) exposed to diet-induced obesity conditions.

Localization and phenotypic characterization of brainstem neurons activated by rimonabant and WIN55,212-2.

The mechanisms by which the CB1 receptor antagonist rimonabant exerts its appetite-suppressing and energy-dissipating effects are still incompletely resolved. To shed further light on the central pathways influenced by CB1 receptor modulation we examined the expression of the immediate early gene c-fos in male Sprague-Dawley rats at 60, 120 and 240 min after intraperitoneal administration of the CB1R antagonist rimonabant (10 mg/kg) and the CB1R agonist WIN55,212-2 (3 mg/kg). Perfusion-fixed brains were processed for immunohistochemistry and the localization of c-Fos immunoreactive neuronal profiles was assessed qualitatively throughout the brain.