Orally bioavailable competitive CCR5 antagonists.
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.
Thoma
Gebhard
G
Novartis Institutes for BioMedical Research, Lichtstrasse 35, WSJ-507.4.12, CH-4056 Basel, Switzerland. gebhard.thoma@pharma.novartis.com
Nuninger
François
F
Schaefer
Marc
M
Akyel
Kayhan G
KG
Albert
Rainer
R
Beerli
Christian
C
Bruns
Christian
C
Francotte
Eric
E
Luyten
Marcel
M
MacKenzie
Duncan
D
Oberer
Lukas
L
Streiff
Markus B
MB
Wagner
Trixie
T
Walter
Hansrudolf
H
Weckbecker
Gisbert
G
Zerwes
Hans-Guenter
HG
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
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