Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases
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- 作者：David A. S ; ham ; Nicola Arnold ; Heinrich Aschauer ; Kamlesh Bala ; Lucy Barker ; Lyndon Brown ; Zarin Brown ; David Budd ; Brian Cox ; Cerys Docx ; Gerald Dubois ; Nicholas Duggan ; Karen Engl ; Brian Everatt ; Marcus Furegati ; Edward Hall ; Frank Kalthoff ; Anna King ; Catherine J. Leblanc ; Jodie Manini ; et al.
- 关键词：BAL ; bronchoalveolar lavage ; BEMP ; 2-tert-butylimino-2-diethylamino-1 ; 3-dimethyl-perhydro-1 ; 3 ; 2-diazaphosphorine ; CCR-3 ; CC chemokine receptor 3 ; CRTh2 ; chemoattractant receptor homologous expressed on Th2 cells ; DK-PGD2 ; 13 ; 14-dihydro-15-keto-PGD2 ; ELSD
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2013
- 出版时间：1 November, 2013
- 年：2013
- 卷：21
- 期：21
- 页码：6582-6591
- 全文大小：1864 K
文摘
Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development.