Pharmacophore Model To Discover OX₁ and OX₂ Orexin Receptor Ligands

Small molecule agonists and antagonists of the orexinergic system have key implications for research and therapeutic purposes. We report a pharmacophore model trained on ∼200 antagonists and prospectively validated by screening a collection of ∼137,000 compounds. The resulting hit list, 395 compounds, was tested for OX₁ and OX₂ receptor activity using calcium mobilization assay in recombinant cell lines. Validation was conducted using both calcium mobilization and [¹²⁵I]-orexin‑A competition binding. Compounds <b>4</b>–<b>7</b> have weak agonist activity and K_i’s in the 1–30 μM range; compounds <b>8</b>–<b>14</b> are antagonists with K_i’s in the 0.1–10 μM range for OX₂ and 1–50 μM for the OX₁ receptor. Docking simulations were used to devise a working hypothesis where two subpockets are important for activation, one between TM5 and TM6 lined by Phe5.42, Tyr5.47, and Tyr6.48 and another above the orthosteric pocket lined by Asp2.65 and Tyr7.32

A Developability-Focused Optimization Approach Allows Identification of in Vivo Fast-Acting Antimalarials: <i>N</i>‑[3-[(Benzimidazol-2-yl)amino]propyl]amides

Malaria continues to be a major global health problem, being particularly devastating in the African population under the age of five. Artemisinin-based combination therapies (ACTs) are the first-line treatment recommended by the WHO to treat Plasmodium falciparum malaria, but clinical resistance against them has already been reported. As a consequence, novel chemotypes are urgently needed. Herein we report a novel, in vivo active, fast-acting antimalarial chemotype based on a benzimidazole core. This discovery is the result of a medicinal chemistry plan focused on improving the developability profile of an antichlamydial chemical class previously reported by our group