title: Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy.
abstract: Here we describe the pharmacologic properties of a series of clinically relevant chemoattractant receptor-homologous molecules expressed on T-helper type 2 (CRTh2) receptor antagonists, including fevipiprant (NVP-QAW039 or QAW039), which is currently in development for the treatment of allergic diseases. [(3)H]-QAW039 displayed high affinity for the human CRTh2 receptor (1.14 ± 0.44 nM) expressed in Chinese hamster ovary cells, the binding being reversible and competitive with the native agonist prostaglandin D2(PGD2). The binding kinetics of QAW039 determined directly using [(3)H]-QAW039 revealed mean kinetic on (kon) and off (koff) values for QAW039 of 4.5 × 10(7)M(-1)min(-1)and 0.048 minute(-1), respectively. Importantly, thekoffof QAW039 (half-life = 14.4 minutes) was >7-fold slower than the slowest reference compound tested, AZD-1981. In functional studies, QAW039 behaved as an insurmountable antagonist of PGD2-stimulated [(35)S]-GTPγS activation, and its effects were not fully reversed by increasing concentrations of PGD2after an initial 15-minute incubation period. This behavior is consistent with its relatively slow dissociation from the human CRTh2 receptor. In contrast for the other ligands tested this time-dependent effect on maximal stimulation was fully reversed by the 15-minute time point, whereas QAW039's effects persisted for >180 minutes. All CRTh2 antagonists tested inhibited PGD2-stimulated human eosinophil shape change, but importantly QAW039 retained its potency in the whole-blood shape-change assay relative to the isolated shape change assay, potentially reflective of its relatively slower off rate from the CRTh2 receptor. QAW039 was also a potent inhibitor of PGD2-induced cytokine release in human Th2 cells. Slow CRTh2 antagonist dissociation could provide increased receptor coverage in the face of pathologic PGD2concentrations, which may be clinically relevant.
authors.affiliation: Novartis Institutes for Biomedical Research, Horsham, West Sussex, UK (D.A.S., M.E.B., D.M.R., E.W., J.R., A.M., S.W., D.A.S., G.D., S.J.C.); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (D.A.Sa., J.R.); Novartis Institutes for Biomedical Research, Basel, Switzerland (C.B.); School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK (D.A.Sy., S.J.C.).
authors.forename: David A
authors.initials: DA
authors.lastname: Sykes
authors.affiliation: Novartis Institutes for Biomedical Research, Horsham, West Sussex, UK (D.A.S., M.E.B., D.M.R., E.W., J.R., A.M., S.W., D.A.S., G.D., S.J.C.); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (D.A.Sa., J.R.); Novartis Institutes for Biomedical Research, Basel, Switzerland (C.B.); School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK (D.A.Sy., S.J.C.).
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Bradley
authors.affiliation: Novartis Institutes for Biomedical Research, Horsham, West Sussex, UK (D.A.S., M.E.B., D.M.R., E.W., J.R., A.M., S.W., D.A.S., G.D., S.J.C.); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (D.A.Sa., J.R.); Novartis Institutes for Biomedical Research, Basel, Switzerland (C.B.); School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK (D.A.Sy., S.J.C.).
authors.forename: Darren M
authors.initials: DM
authors.lastname: Riddy
authors.affiliation: Novartis Institutes for Biomedical Research, Horsham, West Sussex, UK (D.A.S., M.E.B., D.M.R., E.W., J.R., A.M., S.W., D.A.S., G.D., S.J.C.); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (D.A.Sa., J.R.); Novartis Institutes for Biomedical Research, Basel, Switzerland (C.B.); School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK (D.A.Sy., S.J.C.).
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Willard
authors.affiliation: Novartis Institutes for Biomedical Research, Horsham, West Sussex, UK (D.A.S., M.E.B., D.M.R., E.W., J.R., A.M., S.W., D.A.S., G.D., S.J.C.); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (D.A.Sa., J.R.); Novartis Institutes for Biomedical Research, Basel, Switzerland (C.B.); School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK (D.A.Sy., S.J.C.).
authors.forename: John
authors.initials: J
authors.lastname: Reilly
authors.affiliation: Novartis Institutes for Biomedical Research, Horsham, West Sussex, UK (D.A.S., M.E.B., D.M.R., E.W., J.R., A.M., S.W., D.A.S., G.D., S.J.C.); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (D.A.Sa., J.R.); Novartis Institutes for Biomedical Research, Basel, Switzerland (C.B.); School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK (D.A.Sy., S.J.C.).
authors.forename: Asadh
authors.initials: A
authors.lastname: Miah
authors.affiliation: Novartis Institutes for Biomedical Research, Horsham, West Sussex, UK (D.A.S., M.E.B., D.M.R., E.W., J.R., A.M., S.W., D.A.S., G.D., S.J.C.); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (D.A.Sa., J.R.); Novartis Institutes for Biomedical Research, Basel, Switzerland (C.B.); School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK (D.A.Sy., S.J.C.).
authors.forename: Carsten
authors.initials: C
authors.lastname: Bauer
authors.affiliation: Novartis Institutes for Biomedical Research, Horsham, West Sussex, UK (D.A.S., M.E.B., D.M.R., E.W., J.R., A.M., S.W., D.A.S., G.D., S.J.C.); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (D.A.Sa., J.R.); Novartis Institutes for Biomedical Research, Basel, Switzerland (C.B.); School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK (D.A.Sy., S.J.C.).
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Watson
authors.affiliation: Novartis Institutes for Biomedical Research, Horsham, West Sussex, UK (D.A.S., M.E.B., D.M.R., E.W., J.R., A.M., S.W., D.A.S., G.D., S.J.C.); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (D.A.Sa., J.R.); Novartis Institutes for Biomedical Research, Basel, Switzerland (C.B.); School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK (D.A.Sy., S.J.C.) david.sandham@novartis.com StevenCharlton@nottingham.ac.uk.
authors.forename: David A
authors.initials: DA
authors.lastname: Sandham
authors.affiliation: Novartis Institutes for Biomedical Research, Horsham, West Sussex, UK (D.A.S., M.E.B., D.M.R., E.W., J.R., A.M., S.W., D.A.S., G.D., S.J.C.); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (D.A.Sa., J.R.); Novartis Institutes for Biomedical Research, Basel, Switzerland (C.B.); School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK (D.A.Sy., S.J.C.).
authors.forename: Gerald
authors.initials: G
authors.lastname: Dubois
authors.affiliation: Novartis Institutes for Biomedical Research, Horsham, West Sussex, UK (D.A.S., M.E.B., D.M.R., E.W., J.R., A.M., S.W., D.A.S., G.D., S.J.C.); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (D.A.Sa., J.R.); Novartis Institutes for Biomedical Research, Basel, Switzerland (C.B.); School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK (D.A.Sy., S.J.C.) david.sandham@novartis.com StevenCharlton@nottingham.ac.uk.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Charlton
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D018926:Anti-Allergic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D016466:CHO Cells; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D003412:Cricetulus; D015507:Drugs, Investigational / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007210:Indoleacetic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008024:Ligands; D015230:Prostaglandin D2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012995:Solubility; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014316:Tritium
chemical_list: D000085:Acetates; D018926:Anti-Allergic Agents; D015507:Drugs, Investigational; D007210:Indoleacetic Acids; D007211:Indoles; D008024:Ligands; D011725:Pyridines; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D011994:Recombinant Proteins; D014316:Tritium; C569518:AZD1981; C000604875:fevipiprant; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor