Development of CXCR3 antagonists. Part 3: Tropenyl and homotropenyl-piperidine urea derivatives.
The optimization of a series of 1-aryl-3-piperidinyl urea derivatives is described in which incorporation of tropenyl and homotropenyl moieties has led to significant improvements in activity and drug-like properties. Replacement of the central piperidine with an exo-tropanyl unit led to the identification of compound 15 which provides a combination of excellent potency against human and murine receptors, drug-like properties and pharmacokinetics, thus providing a valuable tool for the evaluation of CXCR3 antagonists in models of human disease.
Watson
Robert J
RJ
UCB Inflammation Discovery, Granta Park, Great Abington, Cambridge CB21 6GS, United Kingdom. bob.watson@ucb-group.com
Allen
Daniel R
DR
Birch
Helen L
HL
Chapman
Gayle A
GA
Galvin
Frances C
FC
Jopling
Louise A
LA
Knight
Roland L
RL
Meier
Dorica
D
Oliver
Kathryn
K
Meissner
Johannes W G
JW
Owen
David A
DA
Thomas
Elizabeth J
EJ
Tremayne
Neil
N
Williams
Sophie C
SC
D000818:Animals; D003516:Cycloparaffins / Q000737:chemistry; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
C515187:CXCR3 protein, human; D003516:Cycloparaffins; D010880:Piperidines; D054367:Receptors, CXCR3; D014508:Urea