title: Orally bioavailable competitive CCR5 antagonists.
abstract: The chemokine receptor CCR5 plays an important role in inflammatory and autoimmune disorders as well as in transplant rejection by affecting the trafficking of effector T cells and monocytes to diseased tissues. Antagonists of CCR5 are believed to be of potential therapeutic value for the disorders mentioned above and HIV infection. Here we report on the structure-activity relationship of a new series of highly potent and selective competitive CCR5 antagonists. While all compounds tested were inactive on rodent CCR5, this series includes compounds that cross-react with the cynomolgus monkey (cyno) receptor. One of these compounds, i.e., 26n, has good PK properties in cynos, and its overall favorable profile makes it a promising candidate for in vivo profiling in transplantation and other disease models.
authors.affiliation: Novartis Institutes for BioMedical Research, Lichtstrasse 35, WSJ-507.4.12, CH-4056 Basel, Switzerland. gebhard.thoma@pharma.novartis.com
authors.forename: Gebhard
authors.initials: G
authors.lastname: Thoma
authors.forename: François
authors.initials: F
authors.lastname: Nuninger
authors.forename: Marc
authors.initials: M
authors.lastname: Schaefer
authors.forename: Kayhan G
authors.initials: KG
authors.lastname: Akyel
authors.forename: Rainer
authors.initials: R
authors.lastname: Albert
authors.forename: Christian
authors.initials: C
authors.lastname: Beerli
authors.forename: Christian
authors.initials: C
authors.lastname: Bruns
authors.forename: Eric
authors.initials: E
authors.lastname: Francotte
authors.forename: Marcel
authors.initials: M
authors.lastname: Luyten
authors.forename: Duncan
authors.initials: D
authors.lastname: MacKenzie
authors.forename: Lukas
authors.initials: L
authors.lastname: Oberer
authors.forename: Markus B
authors.initials: MB
authors.lastname: Streiff
authors.forename: Trixie
authors.initials: T
authors.lastname: Wagner
authors.forename: Hansrudolf
authors.initials: H
authors.lastname: Walter
authors.forename: Gisbert
authors.initials: G
authors.lastname: Weckbecker
authors.forename: Hans-Guenter
authors.initials: HG
authors.lastname: Zerwes
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D065100:CCR5 Receptor Antagonists; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002634:Chemotaxis, Leukocyte; D006224:Cricetinae; D018360:Crystallography, X-Ray; D003497:Cyclic N-Oxides; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D008252:Macaca fascicularis; D051379:Mice; D015394:Molecular Structure; D010880:Piperidines; D011743:Pyrimidines; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C485106:(4,6-dimethyl-1-oxypyrimidin-5-yl)(4-diphenylamino-4'-methyl-(1,4')bipiperidinyl-1'-yl)methanone; D065100:CCR5 Receptor Antagonists; D003497:Cyclic N-Oxides; D010880:Piperidines; D011743:Pyrimidines; D011744:Pyrimidinones; D004159:Diphenylamine; D002118:Calcium