β-barrel proteins dictate the effect of core oligosaccharide composition on outer membrane mechanics.

Unlabelled: The outer membrane is the defining structure of Gram-negative bacteria. We previously demonstrated that it is critical for the mechanical integrity of the cell envelope and therefore to the robustness of the bacterial cell as a whole. Here, to determine the key molecules and moieties within the outer membrane that underlie its contribution to cell envelope mechanics, we measured cell-envelope stiffness across several sets of mutants with altered outer-membrane sugar content, protein content, and electric charge.

Re-exploration of the mGlu₁ PAM Ro 07-11401 scaffold: Discovery of analogs with improved CNS penetration despite steep SAR.

This letter describes the re-exploration of the mGlu1 PAM Ro 07-11401 scaffold through a multi-dimensional, iterative parallel synthesis approach. Unlike recent series of mGlu1 PAMs with robust SAR, the SAR around the Ro 07-11401 structure was incredibly steep (only ∼6 of 200 analogs displayed mGlu1 PAM activity), and reminiscent of the CPPHA mGlu5 PAM scaffold. Despite the steep SAR, two new thiazole derivatives were discovered with improved in vitro DMPK profiles and ∼3- to 4-fold improvement in CNS exposure (Kps 1.