168405-44-5Relevant articles and documents
Hit-to-lead evaluation of a novel class of sphingosine 1-phosphate lyase inhibitors
Dinges, Jurgen,Harris, Christopher M.,Wallace, Grier A.,Argiriadi, Maria A.,Queeney, Kara L.,Perron, Denise C.,Dominguez, Eric,Kebede, Tegest,Desino, Kelly E.,Patel, Hetal,Vasudevan, Anil
, p. 2297 - 2302 (2016/04/20)
Inhibition of sphingosine-1-phosphate lyase has recently been proposed as a potential treatment option for inflammatory disorders such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. In this report we describe our hit-to-lead evaluation of the isoxazolecarboxamide 6, a high-throughput screening hit (in vitro IC50 = 1.0 μM, cell IC50 = 1.8 μM), as a novel S1P lyase inhibitor. We were able to establish basic structure-activity relationships around 6 and succeeded in obtaining X-ray structural information which enabled structure-based design. With the discovery of 28, enzyme activity was quickly improved to IC50 = 120 nM and cell potency to IC50 = 230 nM. The main liability in the established isoxazolecarboxamide hit series was determined to be metabolic stability. In particular we identified that future lead-optimization efforts to overcome this problem should focus on blocking the N-dealkylation on the secondary amine.
8-(4-Methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazines: Selective and centrally active corticotropin-releasing factor receptor-1 (CRF1) antagonists
Gilligan, Paul J.,He, Liqi,Clarke, Todd,Tivitmahaisoon, Parcharee,Lelas, Snjezana,Li, Yu-Wen,Heman, Karen,Fitzgerald, Lawrence,Miller, Keith,Zhang, Ge,Marshall, Anne,Krause, Carol,McElroy, John,Ward, Kathyrn,Shen, Helen,Wong, Harvey,Grossman, Scott,Nemeth, Gregory,Zaczek, Robert,Arneric, Stephen P.,Hartig, Paul,Robertson, David W.,Trainor, George
scheme or table, p. 3073 - 3083 (2010/01/16)
This report describes the syntheses and structure-activity relationships of 8-(4-methoxyphenyl)pyrazolo-[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF1) receptor antagonists. CRF1 receptor antagonists may be potential anxiolytic or antidepressant drugs. This research culminated in the discovery of analogue 12-3, which is a potent, selective CRF1 antagonist (hCRF1 IC50 ) 4.7 ± 2.0 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 12-3 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 12-3 has been advanced to clinical trials.
