Dual Glycolate Oxidase/Lactate Dehydrogenase A Inhibitors for Primary Hyperoxaluria.

Both glycolate oxidase (GO) and lactate dehydrogenase A (LDHA) influence the endogenous synthesis of oxalate and are clinically validated targets for treatment of primary hyperoxaluria (PH). We investigated whether dual inhibition of GO and LDHA may provide advantage over single agents in treating PH. Utilizing a structure-based drug design (SBDD) approach, we developed a series of novel, potent, dual GO/LDHA inhibitors. X-ray crystal structures of compound 15 bound to individual GO and LDHA proteins validated our SBDD strategy. Dual inhibitor 7 demonstrated an IC50 of 88 nM for oxalate reduction in an Agxt-knockdown mouse hepatocyte assay. Limited by poor liver exposure, this series of dual inhibitors failed to demonstrate significant PD modulation in an in vivo mouse model. This work highlights the challenges in optimizing in vivo liver exposures for diacid containing compounds and limited benefit seen with dual GO/LDHA inhibitors over single agents alone in an in vitro setting.

The Effect of Diluent Mixture with Upper Critical Solution Temperature on Membrane Formation Process, Microstructure, and Performance of PVDF Hollow Fiber Membrane by TIPS Process.

Thermally induced phase separation (TIPS) is a technique to prepare commercial membrane. However, the quick polymer crystallization during the quenching process will bring about a dense and thick skin layer and thus decrease permeability markedly. In this paper, a diluent mixture with upper critical solution temperature (UCST) was used to prepare polyvinylidene fluoride (PVDF) hollow fiber membrane. That is, the separation between diluent (propylene carbonate (PC)) and non-diluent (dioctyl terephthalate (DOTP)) occurred during the quenching process when the temperature of the dope was lower than 110 °C. The effects of separation between PC and DOTP and the resulting coalescence of DOTP on the PVDF crystallization process, microstructure, and the permeability of the membranes were analyzed. The results showed that the suitable PC/DOTP weight ratio reduced the thickness of the skin layer near the outer surface markedly and resulted in a porous outer surface, and the microstructure evolution process was proposed. The maximum pure water flux for the prepared membrane is up to 128.5 L·m-2·h-1 even in a dry mode without using a hydrophilizing agent. The rejection rate of the carbonic particle is nearly 100%. This study presents a novel and simple way to fabricate the microporous membrane with the interconnected pore structure.

Synthesis of chiral heterocycles by ligand-controlled regiodivergent and enantiospecific Suzuki Miyaura cross-coupling.

Non-aromatic nitrogen- and oxygen-containing heterocycles such as piperidines and pyrans are prevalent components of natural products and pharmaceutical drugs. Although it has been a workhorse as a synthetic method for assembling unsaturated sp(2)-hybridized substrates, transition metal-catalysed cross-coupling chemistry is traditionally not a suitable approach to prepare chiral non-aromatic heterocycles. Several mechanistic issues hamper the coupling of stereogenic secondary sp(3)-hybridized carbon-metal centres. Moreover, use of unsymmetrical allylic boronates in the Suzuki Miyaura cross-coupling is further complicated by the possibility of forming two regioisomeric products. Here we address this two-pronged problem and demonstrate that chiral enantiomerically enriched heterocyclic allylic boronates can be coupled with high stereochemical retention with a wide variety of aryl and alkenyl halides to independently afford both regioisomeric 2- and 4-substituted dihydropyrans and dehydropiperidines in high selectivity. A divergent mechanism is proposed where regiochemistry is governed by the nature of the ligands on the palladium catalyst. This scalable method is applied to the efficient preparation of the neuroactive alkaloid anabasine and the antidepressant drug paroxetine.

Stereoselective preparation of ß-aryl-ß-boronyl enoates and their copper-catalyzed enantioselective conjugate reduction.

A new methodology has been developed for the stereoselective preparation of ß-aryl-ß-boronyl α,ß-unsaturated esters via Heck coupling, and their subsequent copper(I)-catalyzed enantioselective conjugate reduction. Various chiral secondary boronate derivatives can be accessed in excellent yields and good to high levels of enantioselectivity through the efficient copper-catalyzed process using polymethylhydrosiloxane (PMHS) as the hydride source.