Practical Convergent Laboratory-Scale Synthesis of a CCR5 Receptor Antagonist

An efficient laboratory-scale synthesis has been developed for the selective CCR5 antagonist <b>1</b>. The convergent route has a longest linear sequence of nine steps (15 steps overall), and has overall yields of 18–25%. The route has enabled the preparation of 550 g of <b>1</b>

Optimization of potent inhibitors of P. falciparum dihydroorotate dehydrogenase for the treatment of malaria

Inhibition of dihydroorotate dehydrogenase (DHODH) for P. falciparum potentially represents a new treatment option for malaria, since DHODH catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and P. falciparum is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. We report herein the synthesis and structure-activity relationship of a series of 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamides that are potent inhibitors against PfDHODH but do not inhibit the human enzyme. On the basis of efficacy observed in three mouse models of malaria, acceptable safety pharmacology risk assessment and safety toxicology profile in rodents, lack of potential drug-drug interactions, acceptable ADME/pharmacokinetic profile, and projected human dose, 5-(4-cyano-2-methyl-1H-benzo[d]imidazol-1-yl)-N-cyclopropylthiophene-2-carboxamide 2q was identified as a potential drug development candidat

β‑Glucocerebrosidase Modulators Promote Dimerization of β‑Glucocerebrosidase and Reveal an Allosteric Binding Site

β-Glucocerebrosidase (GCase) mutations cause Gaucher’s disease and are a high risk factor in Parkinson’s disease. The implementation of a small molecule modulator is a strategy to restore proper folding and lysosome delivery of degradation-prone mutant GCase. Here, we present a potent quinazoline modulator, <b>JZ-4109</b>, which stabilizes wild-type and N370S mutant GCase and increases GCase abundance in patient-derived fibroblast cells. We then developed a covalent modification strategy using a lysine targeted inactivator (<b>JZ-5029</b>) for <i>in vitro</i> mechanistic studies. By using native top-down mass spectrometry, we located two potentially covalently modified lysines. We obtained the first crystal structure, at 2.2 Å resolution, of a GCase with a noniminosugar modulator covalently bound, and were able to identify the exact lysine residue modified (Lys346) and reveal an allosteric binding site. GCase dimerization was induced by our modulator binding, which was observed by native mass spectrometry, its crystal structure, and size exclusion chromatography with a multiangle light scattering detector. Finally, the dimer form was confirmed by negative staining transmission electron microscopy studies. Our newly discovered allosteric site and observed GCase dimerization provide a new mechanistic insight into GCase and its noniminosugar modulators and facilitate the rational design of novel GCase modulators for Gaucher’s disease and Parkinson’s disease

NOVEL AMINOINDOLE INHIBITORS OF PLASMODIUM FALCIPARUM: IN VIVO EFFICACY AND PRELIMINARY SAFETY ASSESSMENT

Host-parasite interactio