title: Novel pyrrolidine ureas as C-C chemokine receptor 1 (CCR1) antagonists.
abstract: 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.
authors.affiliation: Pharmacopeia, Inc., Cranbury, New Jersey 08512, USA. bmerritt@pcop.com
authors.forename: J Robert
authors.initials: JR
authors.lastname: Merritt
authors.forename: Jinqi
authors.initials: J
authors.lastname: Liu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Quadros
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Morris
authors.forename: Ruiyan
authors.initials: R
authors.lastname: Liu
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Biji
authors.initials: B
authors.lastname: Jacob
authors.forename: Jennifer
authors.initials: J
authors.lastname: Postelnek
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Hicks
authors.forename: Weiqing
authors.initials: W
authors.lastname: Chen
authors.forename: Earl F
authors.initials: EF
authors.lastname: Kimble
authors.forename: W Lynn
authors.initials: WL
authors.lastname: Rogers
authors.forename: Linda
authors.initials: L
authors.lastname: O'Brien
authors.forename: Nicole
authors.initials: N
authors.lastname: White
authors.forename: Hema
authors.initials: H
authors.lastname: Desai
authors.forename: Shalini
authors.initials: S
authors.lastname: Bansal
authors.forename: George
authors.initials: G
authors.lastname: King
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ohlmeyer
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Appell
authors.forename: Maria L
authors.initials: ML
authors.lastname: Webb
mesh_terms: 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
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D011759:Pyrrolidines; D054389:Receptors, CCR1; D014508:Urea