American Chemical Society
jm200365y_si_001.pdf (238.92 kB)

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

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journal contribution
posted on 2011-06-23, 00:00 authored by Kevin J. Hodgetts, 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
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.