Novel Octahydropyrrolo[3,4‑<i>c</i>]pyrroles Are Selective Orexin‑2 Antagonists: SAR Leading to a Clinical Candidate

The preclinical characterization of novel octahydro­pyrrolo­[3,4-<i>c</i>]­pyrroles that are potent and selective orexin-2 antagonists is described. Optimization of physicochemical and DMPK properties led to the discovery of compounds with tissue distribution and duration of action suitable for evaluation in the treatment of primary insomnia. These selective orexin-2 antagonists are proven to promote sleep in rats, and this work ultimately led to the identification of a compound that progressed into human clinical trials for the treatment of primary insomnia. The synthesis, SAR, and optimization of the pharmacokinetic properties of this series of compounds as well as the identification of the clinical candidate, JNJ-42847922 (<b>34</b>), are described herein

Lead Optimization of 5‑Aryl Benzimidazolone- and Oxindole-Based AMPA Receptor Modulators Selective for TARP γ‑8

Glutamate mediates fast excitatory neurotransmission via ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The trafficking and gating properties of AMPA receptors (AMPARs) can be amplified by transmembrane AMPAR regulatory proteins (TARPs), which are often expressed in localized brain regions. Herein, we describe the discovery, lead optimization, and preclinical characterization of 5-arylbenzimidazolone and oxindole-based negative modulators of AMPARs associated with TARP γ-8, the primary TARP found in hippocampus. High-throughput screen lead <b>4</b> was optimized for potency and brain penetration to provide benzimidazolone <b>3</b>, JNJ-55511118. Replacement of the benzimidazolone core in <b>3</b> with an oxindole mitigated reactive metabolite formation and led to the identification of <b>18</b> (GluA1/γ-8 pIC₅₀ = 9.7). Following oral dosing in rats, <b>18</b> demonstrated robust target engagement in hippocampus as assessed by <i>ex vivo</i> autoradiography (ED₅₀ = 0.6 mg/kg, plasma EC₅₀ = 9 ng/mL)