Discovery of 4-(5-Membered)Heteroarylether-6-methylpicolinamide Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5.

This Letter details our efforts to develop novel, non-acetylene-containing metabotropic glutamate receptor subtype 5 (mGlu) negative allosteric modulators (NAMs) with improved pharmacological properties. This endeavor involved replacing the ether-linked pyrimidine moiety, a metabolic liability, with various 5-membered heterocycles. From this exercise, we identified , a highly brain penetrant and selective mGlu NAM which displayed moderate potency against both human and rat mGlu.

Discovery of VU6024578/BI02982816: An mGlu Positive Allosteric Modulator with Efficacy in Preclinical Antipsychotic and Cognition Models.

Herein, we report progress toward a metabotropic glutamate receptor subtype 1 (mGlu) positive allosteric modulator (PAM) clinical candidate and the discovery of VU6024578/BI02982816. From a weak high-throughput screening hit (VU0538160, EC > 10 μM, 71% Glu), optimization efforts improved functional potency over 185-fold to deliver the selective (inactive on mGlu) and CNS penetrant (rat K = 0.99, K = 0.

Discovery of VU0467319: an M Positive Allosteric Modulator Candidate That Advanced into Clinical Trials.

Herein we detail the of VU0467319 (VU319), an M Positive Allosteric Modulator (PAM) clinical candidate that successfully completed a Phase I Single Ascending Dose (SAD) clinical trial. VU319 () is a moderately potent M PAM (M PAM EC = 492 nM ± 2.9 nM, 71.

Recent trends and risk factors for chemical and physical restraint use in the emergency department evaluation and treatment of trauma patients.

Background: Despite research linking chemical and physical restraints to negative outcomes including unplanned intubations and psychological distress, there is little guidance for their use in the care of trauma patients. We used institutional data to describe recent trends in chemical and physical restraint in the emergency department evaluation and treatment of trauma patients and to identify characteristics associated with their use.

Methods: This study includes adult trauma activations at a United States urban level I trauma center from January 2016 to July 2022.