Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases

Autor:	Brian Cox, David C. Budd, Anna King, Gareth Williams, Nicholas Duggan, Rowan Stringer, Marcus Furegati, Alfred Schmidt, Josef G. Meingassner, Kamlesh Bala, Brian Everatt, Katharine L. Turner, Jennifer Simmons, Cerys Docx, Catherine Leblanc, Gerald Dubois, Frank Kalthoff, Caroline Wilson, Lucy Barker, Karen England, Nicola Arnold, John Westwick, Edward Charles Hall, Bindi Sohal, Jennifer Willis, Heinrich Aschauer, David Andrew Sandham, Rachael Profit, Zarin Brown, Lyndon Nigel Brown, Simon J. Watson, Jodie Manini, Christoph Walker, Matthew Thomas
Rok vydání:	2013
Předmět:	medicine.drug_class High-throughput screening Receptors Prostaglandin Clinical Biochemistry Drug Evaluation Preclinical Administration Oral Pharmaceutical Science CHO Cells Pharmacology Dermatitis Contact Biochemistry Rats Sprague-Dawley Mice Structure-Activity Relationship Cricetulus Th2 Cells Cricetinae Drug Discovery Hypersensitivity medicine Animals Humans Potency NVP-QAV680 Receptors Immunologic Molecular Biology Mice Inbred BALB C Chemistry Organic Chemistry Indolizines Eosinophil Receptor antagonist In vitro Rats Bioavailability Eosinophils Disease Models Animal medicine.anatomical_structure Lymphocyte activation Molecular Medicine Half-Life Protein Binding
Zdroj:	Bioorganic & Medicinal Chemistry. 21:6582-6591
ISSN:	0968-0896
DOI:	10.1016/j.bmc.2013.08.025
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1cc63a5fbb90947c1f906a4739b943b4 https://doi.org/10.1016/j.bmc.2013.08.025 Zobrazit plný text záznamu Full Text from ScienceDirect