1. Academic Validation
  2. Discovery of N-(1-ethylpropyl)-[3-methoxy-5-(2-methoxy-4-trifluoromethoxyphenyl)-6-methyl-pyrazin-2-yl]amine 59 (NGD 98-2): an orally active corticotropin releasing factor-1 (CRF-1) receptor antagonist

Discovery of N-(1-ethylpropyl)-[3-methoxy-5-(2-methoxy-4-trifluoromethoxyphenyl)-6-methyl-pyrazin-2-yl]amine 59 (NGD 98-2): an orally active corticotropin releasing factor-1 (CRF-1) receptor antagonist

  • J Med Chem. 2011 Jun 23;54(12):4187-206. doi: 10.1021/jm200365y.
Kevin J Hodgetts 1 Ping Ge Taeyoung Yoon Stéphane De Lombaert Robbin Brodbeck Michael Gulianello Andrzej Kieltyka Raymond F Horvath John H Kehne James E Krause George D Maynard Diane Hoffman Younglim Lee Laurence Fung Dario Doller
Affiliations

Affiliation

  • 1 Neurogen Corporation, 35 Northeast Industrial Road, Branford, Connecticut 06405, United States. khodgetts@galenea.com
Abstract

The design, synthesis, and structure-activity relationships of a novel series of pyrazines, acting as corticotropin releasing factor-1 (CRF-1) receptor antagonists, are described. Synthetic methodologies were developed to prepare a number of substituted pyrazine cores utilizing regioselective halogenation and chemoselective derivatization. Noteworthy, an efficient 5-step synthesis was developed for the lead compound 59 (NGD 98-2), which required no chromatography. Compound 59 was characterized as an orally bioavailable, brain penetrant, and highly selective CRF-1 receptor antagonist. Occupancy of rat brain CRF-1 receptors was quantified using ex vivo receptor occupancy assays, using both brain tissue homogenates as well as brain slices receptor autoradiography. Behaviorally, oral administration of 59 significantly antagonized CRF-induced locomotor activity at doses as low as 10 mg/kg and dose-dependently reduced the restraint stress-induced ACTH increases.

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