2. Academic Validation
  3. Discovery of TAK-041: a Potent and Selective GPR139 Agonist Explored for the Treatment of Negative Symptoms Associated with Schizophrenia

Discovery of TAK-041: a Potent and Selective GPR139 Agonist Explored for the Treatment of Negative Symptoms Associated with Schizophrenia

  • J Med Chem. 2021 Aug 12;64(15):11527-11542. doi: 10.1021/acs.jmedchem.1c00820.
Holly A Reichard 1,  Hans H Schiffer 1,  Holger Monenschein 1,  Josephine M Atienza 1,  Gerard Corbett 2,  Alton W Skaggs 1,  Deanna R Collia 1,  William J Ray 1,  Jordi Serrats 1,  Joshua Bliesath 1,  Nidhi Kaushal 1,  Betty P Lam 1,  Alejandro Amador-Arjona 1,  Lisa Rahbaek 1,  Donavon J McConn 1,  Victoria J Mulligan 2,  Nicola Brice 2,  Philip L R Gaskin 2,  Jackie Cilia 2,  Stephen Hitchcock 1
Affiliations

Affiliations

  • 1 Takeda California, Inc., 9625 Towne Centre Drive, San Diego, California 92121, United States.
  • 2 Takeda Cambridge Ltd., 418 Cambridge Science Park, Cambridge, Cambridgeshire CB4 0PZ, U.K.
PMID: 34260228 DOI: 10.1021/acs.jmedchem.1c00820
Abstract

The orphan G-protein-coupled receptor GPR139 is highly expressed in the habenula, a small brain nucleus that has been linked to depression, schizophrenia (SCZ), and substance-use disorder. High-throughput screening and a medicinal chemistry structure-activity relationship strategy identified a novel series of potent and selective benzotriazinone-based GPR139 agonists. Herein, we describe the chemistry optimization that led to the discovery and validation of multiple potent and selective in vivo GPR139 Agonist tool compounds, including our clinical candidate TAK-041, also known as NBI-1065846 (compound 56). The pharmacological characterization of these GPR139 agonists in vivo demonstrated GPR139-agonist-dependent modulation of habenula cell activity and revealed consistent in vivo efficacy to rescue social interaction deficits in the BALB/c mouse strain. The clinical GPR139 Agonist TAK-041 is being explored as a novel drug to treat negative symptoms in SCZ.

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