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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Ng HP,May K,Bauman JG,Ghannam A,Islam I,Liang M,Horuk R,Hesselgesser J,Snider RM,Perez HD,Morrissey MMdoi
10.1021/jm990316lkeywords:
subject
Has Abstractpub_date
1999-11-04 00:00:00pages
4680-94issue
22eissn
0022-2623issn
1520-4804pii
jm990316ljournal_volume
42pub_type
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