2. Academic Validation
  3. Discovery of VU6024578/BI02982816: An mGlu1 Positive Allosteric Modulator with Efficacy in Preclinical Antipsychotic and Cognition Models

Discovery of VU6024578/BI02982816: An mGlu1 Positive Allosteric Modulator with Efficacy in Preclinical Antipsychotic and Cognition Models

  • J Med Chem. 2024 Dec 26;67(24):22291-22312. doi: 10.1021/acs.jmedchem.4c02554.
Carson W Reed 1,  Jacob F Kalbfleisch 1,  Jeremy A Turkett 1,  Trevor A Trombley 1,  Anthony F Nastase 1,  Paul K Spearing 1,  Daniel H Haymer 1,  Mohammad Moshin Sarwar 1,  Marc Quitalig 1,  Jonathan W Dickerson,  Annie L Blobaum 1,  Olivier Boutaud 1,  Patrizia Voehringer 2,  Niklas Schuelert 2,  Hyekyung P Cho 1,  Colleen M Niswender 1,  Jerri M Rook 1,  Henning Priepke 2,  Daniel Ursu 2,  P Jeffrey Conn 1,  Bruce J Melancon 1,  Craig W Lindsley
Affiliations

Affiliations

  • 1 Warren Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37067, Unites States.
  • 2 Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach 88397, Germany.
PMID: 39665415 DOI: 10.1021/acs.jmedchem.4c02554
Abstract

Herein, we report progress toward a metabotropic glutamate receptor subtype 1 (mGlu1) positive allosteric modulator (PAM) clinical candidate and the discovery of VU6024578/BI02982816. From a weak high-throughput screening hit (VU0538160, EC50 > 10 μM, 71% Glumax), optimization efforts improved functional potency over 185-fold to deliver the selective (inactive on mGlu2-5,7,8) and CNS penetrant (rat Kp = 0.99, Kp,uu = 0.82; MDCK-MDR1 ER = 1.7, Papp = 73 × 10-6 cm/s) mGlu1 PAM (VU6024578/BI02982816, EC50 = 54 nM, 83% Glumax). An excellent rat pharmacokinetic profile allowed the evaluation of VU6024578/BI02982816 in both amphetamine-induced hyperlocomotion (minimum effective dose (MED) = 3 mg/kg, p.o.) and MK-801 induced disruptions of novel object recognition (MED = 10 mg/kg p.o.), thus providing efficacy in preclinical models of psychosis and cognition. However, unanticipated AEs in dog prevented further consideration as a candidate. Thus, VU6024578/BI02982816 can serve as a best-in-class in vivo rodent tool to study selective mGlu1 activation.

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