Pharmacological characterization of AZD5069, a slowly reversible CXC chemokine receptor 2 antagonist.
In normal physiologic responses to injury and infection, inflammatory cells enter tissue and sites of inflammation through a chemotactic process regulated by several families of proteins, including inflammatory chemokines, a family of small inducible cytokines. In neutrophils, chemokines chemokine (CXC motif) ligand 1 (CXCL1) and CXCL8 are potent chemoattractants and activate G protein-coupled receptors CXC chemokine receptor 1 (CXCR1) and CXCR2. Several small-molecule antagonists of CXCR2 have been developed to inhibit the inflammatory responses mediated by this receptor. Here, we present the data describing the pharmacology of AZD5069 [N-(2-(2,3-difluorobenzylthio)-6-((2R,3S)-3,4-dihydroxybutan-2-yloxy)[2,4,5,6-(13)C4, 1,3-(15)N2]pyrimidin-4-yl)azetidine-1-sulfonamide,[(15)N2,(13)C4]N-(2-(2,3-difluoro-6-[3H]-benzylthio)-6-((2R,3S)-3,4-dihydroxybutan-2-yloxy)pyrimidin-4-yl)azetidine-1-sulfonamide], a novel antagonist of CXCR2. AZD5069 was shown to inhibit binding of radiolabeled CXCL8 to human CXCR2 with a pIC50 value of 9.1. Furthermore, AZD5069 inhibited neutrophil chemotaxis, with a pA2 of approximately 9.6, and adhesion molecule expression, with a pA2 of 6.9, in response to CXCL1. AZD5069 was a slowly reversible antagonist of CXCR2 with effects of time and temperature evident on the pharmacology and binding kinetics. With short incubation times, AZD5069 appeared to have an antagonist profile with insurmountable antagonism of calcium response curves. This behavior was also observed in vivo in an acute lipopolysaccharide-induced lung inflammation model. Altogether, the data presented here show that AZD5069 represents a novel, potent, and selective CXCR2 antagonist with potential as a therapeutic agent in inflammatory conditions.
Departments of Discovery Sciences (D.J.N.) and Oncology (C.P.), AstraZeneca R&D, Alderley Park, United Kingdom; Biosciences, AstraZeneca R&D Charnwood, Loughborough, Leicestershire, United Kingdom (K.W., F.M., A.G.); and Biosciences, AstraZeneca R&D, Mölndal, Sweden (I.D., C.K.M.).
David J
DJ
Nicholls
Departments of Discovery Sciences (D.J.N.) and Oncology (C.P.), AstraZeneca R&D, Alderley Park, United Kingdom; Biosciences, AstraZeneca R&D Charnwood, Loughborough, Leicestershire, United Kingdom (K.W., F.M., A.G.); and Biosciences, AstraZeneca R&D, Mölndal, Sweden (I.D., C.K.M.).
Katherine
K
Wiley
Departments of Discovery Sciences (D.J.N.) and Oncology (C.P.), AstraZeneca R&D, Alderley Park, United Kingdom; Biosciences, AstraZeneca R&D Charnwood, Loughborough, Leicestershire, United Kingdom (K.W., F.M., A.G.); and Biosciences, AstraZeneca R&D, Mölndal, Sweden (I.D., C.K.M.).
Ian
I
Dainty
Departments of Discovery Sciences (D.J.N.) and Oncology (C.P.), AstraZeneca R&D, Alderley Park, United Kingdom; Biosciences, AstraZeneca R&D Charnwood, Loughborough, Leicestershire, United Kingdom (K.W., F.M., A.G.); and Biosciences, AstraZeneca R&D, Mölndal, Sweden (I.D., C.K.M.).
Fraser
F
MacIntosh
Departments of Discovery Sciences (D.J.N.) and Oncology (C.P.), AstraZeneca R&D, Alderley Park, United Kingdom; Biosciences, AstraZeneca R&D Charnwood, Loughborough, Leicestershire, United Kingdom (K.W., F.M., A.G.); and Biosciences, AstraZeneca R&D, Mölndal, Sweden (I.D., C.K.M.).
Caroline
C
Phillips
Departments of Discovery Sciences (D.J.N.) and Oncology (C.P.), AstraZeneca R&D, Alderley Park, United Kingdom; Biosciences, AstraZeneca R&D Charnwood, Loughborough, Leicestershire, United Kingdom (K.W., F.M., A.G.); and Biosciences, AstraZeneca R&D, Mölndal, Sweden (I.D., C.K.M.).
Alasdair
A
Gaw
Departments of Discovery Sciences (D.J.N.) and Oncology (C.P.), AstraZeneca R&D, Alderley Park, United Kingdom; Biosciences, AstraZeneca R&D Charnwood, Loughborough, Leicestershire, United Kingdom (K.W., F.M., A.G.); and Biosciences, AstraZeneca R&D, Mölndal, Sweden (I.D., C.K.M.) carina.karrman-mardh@astrazeneca.com.
Carina Kärrman
CK
Mårdh
D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007700:Kinetics; D008070:Lipopolysaccharides / Q000009:adverse effects; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013696:Temperature
D039481:CD11b Antigen; D016209:Interleukin-8; D008070:Lipopolysaccharides; C000597960:N-(2-(2,3-difluoro-6-benzylthio)-6-(3,4-dihydroxybutan-2-yloxy)pyrimidin-4-yl)azetidine-1-sulfonamide; D011743:Pyrimidines; D023063:Receptors, Interleukin-8B; D013449:Sulfonamides; D002118:Calcium