Macrocyclic Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonists.

Macrocyclic retinoic acid receptor-related orphan receptor C2 (RORC2) inverse agonists have been designed with favorable properties for topical administration. Inspired by the unanticipated bound conformation of an acyclic sulfonamide-based RORC2 ligand from cocrystal structure analysis, macrocyclic linker connections between the halves of the molecule were explored. Further optimization of analogues was accomplished to maximize potency and refine physiochemical properties (MW, lipophilicity) best suited for topical application. Compound 14 demonstrated potent inhibition of interleukin-17A (IL-17A) production by human Th17 cells and in vitro permeation through healthy human skin achieving high total compound concentration in both skin epidermis and dermis layers.

Synthesis of Deuterated Heterocycles with Me2NCD(OMe)2 and Evaluation of the Products for Metabolism by Aldehyde Oxidase.

The metabolic oxidation of drug-like small molecules by aldehyde oxidase (AO) has commonly been mitigated through the incorporation of deuterium at the oxidation site. We report that dimethylformamide dimethyl acetal and related compounds undergo rapid CH to CD isotopic exchange upon exposure to methanol-d and similar deuterated alcohols. This isotopic exchange process can be used to synthesize Me2NCD(OMe)2 and has significant implications for the use of Me2NCD(OMe)2 in the synthesis of specifically deuterium-labeled compounds. The application of Me2NCD(OMe)2 to the synthesis of various heterocycles that have been associated with AO metabolism is described, and we report the impact of deuteration on the rate of in vitro AO-mediated metabolism.

Tubulin-binding cofactor E-like (TBCEL), the protein product of the mulet gene, is required in the germline for the regulation of inter-flagellar microtubule dynamics during spermatid individualization.

Individual sperm cells are resolved from a syncytium during late step of spermiogenesis known as individualization, which is accomplished by an Individualization Complex (IC) composed of 64 investment cones. mulet encodes Tubulin-binding cofactor E-like (TBCEL), suggesting a role for microtubule dynamics in individualization. Indeed, a population of ∼100 cytoplasmic microtubules fails to disappear in mulet mutant testes during spermatogenesis. This persistence, detected using epi-fluorescence and electron microscopy, suggests that removal of these microtubules by TBCEL is a prerequisite for individualization. Immunofluorescence reveals TBCEL expression in elongated spermatid cysts. In addition, testes from mulet mutant males were rescued to wild type using tubulin-Gal4 to drive TBCEL expression, indicating that the mutant phenotype is caused by the lack of TBCEL. Finally, RNAi driven by bam-GAL4 successfully phenocopied mulet, confirming that mulet is required in the germline for individualization. We propose a model in which the cytoplasmic microtubules serve as alternate tracks for investment cones in mulet mutant testes.This article has an associated First Person interview with the first author of the paper.