Ecological sustainability and high-quality development of the Yellow River Delta in China based on the improved ecological footprint model.

Aiming at the traditional ecological footprint model, the improved ecological footprint of the carbon footprint effectively makes up for the singularity of the ecological footprint's consideration of carbon emissions, and plays an important role in promoting high-quality development and ecological sustainability. This paper selects 2015, 2018 and 2020 as important time points for the study, corrects the ecological footprint parameter factors based on net primary productivity (NPP), measures the ecological footprint after the improvement of the carbon footprint, studies the spatial and temporal variation in the ecological footprint at the 100-m grid scale with the support of IPCC greenhouse gas inventory analysis, and analyzes the current ecological conservation status of the Yellow River Delta. Additionally, in the context of a low carbon economy, the decoupling index of carbon emissions and GDP is extended to the evaluation and analysis of high-quality development. The study showed that (1) the ecological footprint of the Yellow River Delta has increased year by year, from 0.721 hm2·person- 1 to 0.758 hm2·person- 1, an average annual increase of 2.9%; the ecological carrying capacity has decreased from 0.40 hm2·person- 1 to 0.31 hm2·person- 1, an overall decrease of 28.59%. (2) The overall ecological deficit of the Yellow River Delta grid is lightly overloaded, with most of the ecological surplus occurring in the northern and eastern parts of the study area and a few moderate and heavy overloads in the center of the core area where there is a lot of built-up land and the area is small and easy to gather. (3) Based on the low-carbon economy analysis, 2015, 2017 and 2020 reach absolute decoupling and are in the ideal scenario. However, in the rest of the years, carbon emissions and economic development are still in a large contradiction, and decoupling has fluctuated and varied greatly in the last six years. The effective combination of ecological footprint and low carbon economy analysis provides an important theoretical basis for improving ecological conservation and achieving high-quality development.

Discovery of MK-8719, a Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies.

Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Beginning with carbohydrate-based lead molecules, we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high central nervous system (CNS) exposure, metabolic stability, favorable pharmacokinetics, and robust in vivo pharmacodynamic response. Herein, we describe the medicinal chemistry and pharmacological studies that led to the identification of (3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5H-pyrano[3,2-d]thiazole-6,7-diol 42 (MK-8719), a highly potent and selective OGA inhibitor with excellent CNS penetration that has been advanced to first-in-human phase I clinical trials.

Discovery of agonists of cannabinoid receptor 1 with restricted central nervous system penetration aimed for treatment of gastroesophageal reflux disease.

Agonists of the cannabinoid receptor 1 (CB1) have been suggested as possible treatments for a range of medical disorders including gastroesophageal reflux disease (GERD). While centrally acting cannabinoid agonists are known to produce psychotropic effects, it has been suggested that the CB1 receptors in the periphery could play a significant role in reducing reflux. A moderately potent and highly lipophilic series of 2-aminobenzamides was identified through focused screening of GPCR libraries. Development of this series focused on improving potency and efficacy at the CB1 receptor, reducing lipophilicity and limiting the central nervous system (CNS) exposure while maintaining good oral absorption. Improvement of the series led to compounds having excellent potency at the CB1 receptor and high levels of agonism, good physical and pharmacokinetic properties, and low penetration into the CNS. A range of compounds demonstrated a dose-dependent inhibition of transient lower esophageal sphincter relaxations in a dog model.

N-Methyl-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamides as a novel class of cannabinoid receptors agonists with low CNS penetration.

Cannabinoid CB(1) receptor agonists exhibit potent analgesic effects in rodents and humans, but their clinical utility as analgesic drugs is often limited by centrally mediated side effects. We report herein the preparation of N-methyl-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamides as a novel class of hCB(1)/hCB(2) dual agonists with attractive physicochemical properties. More specifically, (R)-N,9-dimethyl-N-(4-(methylamino)-4-oxobutyl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide, displayed an extremely low level of CNS penetration (Rat Cbr/Cplasma=0.005 or 0.5%) and was devoid of CNS side effects during pharmaco-dynamic testing.

Novel benzimidazole derivatives as selective CB2 agonists.

The preparation and evaluation of a novel class of CB2 agonists based on a benzimidazole moiety are reported. They showed binding affinities up to 1nM towards the CB2 receptor with partial to full agonist potencies. They also demonstrated good to excellent selectivity (>1000-fold) over the CB1 receptor.