Novel pyrrolidine ureas as C-C chemokine receptor 1 (CCR1) antagonists.
Monocyte infiltration is implicated in a variety of diseases including multiple myeloma, rheumatoid arthritis, and multiple sclerosis. C-C chemokine receptor 1 (CCR1) is a chemokine receptor that upon stimulation, particularly by macrophage inflammatory protein 1alpha (MIP-1alpha) and regulated on normal T-cell expressed and secreted (RANTES), mediates monocyte trafficking to sites of inflammation. High throughput screening of our combinatorial collection identified a novel, moderately potent CCR1 antagonist 3. The library hit 3 was optimized to the advanced lead compound 4. Compound 4 inhibited CCR1 mediated chemotaxis of monocytes with an IC(50) of 20 nM. In addition, the compound was highly selective over other chemokine receptors. It had good microsomal stability when incubated with rat and human liver microsomes and showed no significant cytochrome P450 (CYP) inhibition. Pharmacokinetic evaluation of the compound in the rat showed good oral bioavailability.
Merritt
J Robert
JR
Pharmacopeia, Inc., Cranbury, New Jersey 08512, USA. bmerritt@pcop.com
Liu
Jinqi
J
Quadros
Elizabeth
E
Morris
Michelle L
ML
Liu
Ruiyan
R
Zhang
Rui
R
Jacob
Biji
B
Postelnek
Jennifer
J
Hicks
Catherine M
CM
Chen
Weiqing
W
Kimble
Earl F
EF
Rogers
W Lynn
WL
O'Brien
Linda
L
White
Nicole
N
Desai
Hema
H
Bansal
Shalini
S
King
George
G
Ohlmeyer
Michael J
MJ
Appell
Kenneth C
KC
Webb
Maria L
ML
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D002634:Chemotaxis, Leukocyte; D065607:Cytochrome P-450 Enzyme Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008862:Microsomes, Liver / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D011759:Pyrrolidines; D054389:Receptors, CCR1; D014508:Urea