1188407-45-5Relevant articles and documents
Development of an efficient synthesis of two CRF antagonists for the treatment of neurological disorders
Leahy, David K.,Li, Jun,Sausker, Justin B.,Zhu, Jason,Fitzgerald, Monica A.,Lai, Chiajen,Buono, Frederic G.,Braem, Alan,De Mas, Nuria,Manaloto, Zerene,Lo, Ehrlic,Merkl, William,Su, Bao-Ning,Gao, Qi,Ng, Alicia T.,Hartz, Richard A.
, p. 1221 - 1228 (2011/04/17)
BMS-764459 (1) and BMS-763534 (2) are CRF1 antagonists for the treatment of neurological disorders such as depression and anxiety. An efficient synthesis of 1 and 2 is described, which features an efficient palladium-catalyzed cyanation of a 5-chloropyraz
A strategy to minimize reactive metabolite formation: Discovery of (S)-4-(1-cyclopropyl-2-methoxyethyl)-6-[6-(difluoromethoxy)-2, 5-dimethylpyridin-3-ylamino]-5-oxo-4,5-dihydropyrazine-2-carbonitrile as a potent, orally bioavailable corticotropin-releasing factor-1 receptor antagonist
Hartz, Richard A.,Ahuja, Vijay T.,Zhuo, Xiaoliang,Mattson, Ronald J.,Denhart, Derek J.,Deskus, Jeffrey A.,Vrudhula, Vivekananda M.,Pan, Senliang,Ditta, Jonathan L.,Shu, Yue-Zhong,Grace, James E.,Lentz, Kimberley A.,Lelas, Snjezana,Li, Yu-Wen,Molski, Thaddeus F.,Krishnananthan, Subramaniam,Wong, Henry,Qian-Cutrone, Jingfang,Schartman, Richard,Denton, Rex,Lodge, Nicholas J.,Zaczek, Robert,Macor, John E.,Bronson, Joanne J.
experimental part, p. 7653 - 7668 (2010/09/03)
Detailed metabolic characterization of 8, an earlier lead pyrazinone-based corticotropin-releasing factor-1 (CRF1) receptor antagonist, revealed that this compound formed significant levels of reactive metabolites, as measured by in vivo and in vitro biotransformation studies. This was of particular concern due to the body of evidence suggesting that reactive metabolites may be involved in idiosyncratic drug reactions. Further optimization of the structure-activity relationships and in vivo properties of pyrazinone-based CRF1 receptor antagonists and studies to assess the formation of reactive metabolites led to the discovery of 19e, a high affinity CRF1 receptor antagonist (IC50= 0.86 nM) wherein GSH adducts were estimated to be only 0.1% of the total amount of drug-related material excreted through bile and urine, indicating low levels of reactive metabolite formation in vivo. Anovel 6-(difluoromethoxy)-2,5-dimethylpyridin-3- amine group in 19e contributed to the potency and improved in vivo properties of this compound and related analogues. 19e had excellent pharmacokinetic properties in rats and dogs and showed efficacy in the defensive withdrawal model of anxiety in rats. The lowest efficacious dose was 1.8 mg/kg. The results of a two-week rat safety study with 19e indicated that this compound was well-tolerated.
