title: Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases.
abstract: 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.
authors.affiliation: Novartis Institutes for Biomedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom. Electronic address: david.sandham@novartis.com.
authors.forename: David A
authors.initials: DA
authors.lastname: Sandham
authors.forename: Nicola
authors.initials: N
authors.lastname: Arnold
authors.forename: Heinrich
authors.initials: H
authors.lastname: Aschauer
authors.forename: Kamlesh
authors.initials: K
authors.lastname: Bala
authors.forename: Lucy
authors.initials: L
authors.lastname: Barker
authors.forename: Lyndon
authors.initials: L
authors.lastname: Brown
authors.forename: Zarin
authors.initials: Z
authors.lastname: Brown
authors.forename: David
authors.initials: D
authors.lastname: Budd
authors.forename: Brian
authors.initials: B
authors.lastname: Cox
authors.forename: Cerys
authors.initials: C
authors.lastname: Docx
authors.forename: Gerald
authors.initials: G
authors.lastname: Dubois
authors.forename: Nicholas
authors.initials: N
authors.lastname: Duggan
authors.forename: Karen
authors.initials: K
authors.lastname: England
authors.forename: Brian
authors.initials: B
authors.lastname: Everatt
authors.forename: Marcus
authors.initials: M
authors.lastname: Furegati
authors.forename: Edward
authors.initials: E
authors.lastname: Hall
authors.forename: Frank
authors.initials: F
authors.lastname: Kalthoff
authors.forename: Anna
authors.initials: A
authors.lastname: King
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Leblanc
authors.forename: Jodie
authors.initials: J
authors.lastname: Manini
authors.forename: Josef
authors.initials: J
authors.lastname: Meingassner
authors.forename: Rachael
authors.initials: R
authors.lastname: Profit
authors.forename: Alfred
authors.initials: A
authors.lastname: Schmidt
authors.forename: Jennifer
authors.initials: J
authors.lastname: Simmons
authors.forename: Bindi
authors.initials: B
authors.lastname: Sohal
authors.forename: Rowan
authors.initials: R
authors.lastname: Stringer
authors.forename: Matthew
authors.initials: M
authors.lastname: Thomas
authors.forename: Katharine L
authors.initials: KL
authors.lastname: Turner
authors.forename: Christoph
authors.initials: C
authors.lastname: Walker
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Watson
authors.forename: John
authors.initials: J
authors.lastname: Westwick
authors.forename: Jennifer
authors.initials: J
authors.lastname: Willis
authors.forename: Gareth
authors.initials: G
authors.lastname: Williams
authors.forename: Caroline
authors.initials: C
authors.lastname: Wilson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003877:Dermatitis, Contact / Q000188:drug therapy; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy; D007212:Indolizines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D007212:Indolizines; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C588117:NVP-QAV680; C036293:prostaglandin D2 receptor
keywords: 13,14-dihydro-15-keto-PGD(2); 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine; Allergy; BAL; BEMP; CC chemokine receptor 3; CCR-3; CRTh2; CRTh2 receptor antagonist; DK-PGD(2); ELSD; FITC; GLP; PGD(2); SC; bronchoalveolar lavage; chemoattractant receptor homologous expressed on Th2 cells; evaporative light scattering detection; fluorescein isothiocyanate; good laboratory practice; prostaglandin D(2); shape change