title: Discovery of novel non-peptide CCR1 receptor antagonists.
abstract: Ligands for the CCR1 receptor (MIP-1alpha and RANTES) have been implicated in a number of chronic inflammatory diseases, most notably multiple sclerosis and rheumatoid arthritis. Because these ligands share a common receptor, CCR1, we sought to discover antagonists for this receptor as an approach to treating these disorders. A novel series of 4-hydroxypiperidines has been discovered by high throughput screening (HTS) which potently inhibits the binding of MIP-1alpha and RANTES to the recombinant human CCR1 chemokine receptor. The structure-activity relationships of various segments of this template are described as the initial HTS lead 1 was optimized synthetically to the highly potent receptor antagonist 6s. This compound has been shown to have at least 200-fold selectivity for inhibition of CCR1 over other human 7-TM receptors, including other chemokine receptors. In addition, data obtained from in vitro functional assays demonstrate the functional antagonism of compound 6s and structurally related analogues against the CCR1 receptor in a concentration dependent manner. The discovery and optimization of potent and selective CCR1 receptor antagonists represented by compound 6s potentially represent a novel approach to the treatment of chronic inflammatory diseases.
authors.affiliation: Department of Discovery Research, Berlex Biosciences, 15049 San Pablo Avenue, Richmond, California 94804-0099, USA.
authors.forename: H P
authors.initials: HP
authors.lastname: Ng
authors.forename: K
authors.initials: K
authors.lastname: May
authors.forename: J G
authors.initials: JG
authors.lastname: Bauman
authors.forename: A
authors.initials: A
authors.lastname: Ghannam
authors.forename: I
authors.initials: I
authors.lastname: Islam
authors.forename: M
authors.initials: M
authors.lastname: Liang
authors.forename: R
authors.initials: R
authors.lastname: Horuk
authors.forename: J
authors.initials: J
authors.lastname: Hesselgesser
authors.forename: R M
authors.initials: RM
authors.lastname: Snider
authors.forename: H D
authors.initials: HD
authors.lastname: Perez
authors.forename: M M
authors.initials: MM
authors.lastname: Morrissey
mesh_terms: D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism / Q000494:pharmacology; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C401389:4-(4-chlorophenyl)-4-hydroxy-alpha,alpha-diphenyl-1-piperidinepentanenitrile; D000893:Anti-Inflammatory Agents; C515300:CCR1 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019402:Macrophage Inflammatory Proteins; D009570:Nitriles; D010880:Piperidines; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D002118:Calcium