Selective CCR1 antagonist
Ligands for the CCR1 receptor (MIP-1α and RANTES) have been implicated in plenty of chronic inflammatory diseases, most notably multiple sclerosis and rheumatoid arthritis. BX 513 is a novel non-peptide CCR1 receptor antagonists.
In vitro: BX 513 has been shown to have at least 200-fold selectivity for CCR1 inhibition over other human 7-TM receptors, including other chemokine receptors. In addition, data obtained from in-vitro functional assays demonstrated the functional antagonism of BX 513 and structurally related analogues against the CCR1 receptor in a dose-dependent manner [1]. BX 513 also showed concentration-dependent inhibition of MIP-1α-induced extracellular acidification and Ca2+ mobilization demonstrating functional antagonism. When given alone, the compound did not elicit any responses, suggesting the absence of intrinsic agonist activity. BX 513 inhibited MIP-1α- and RANTES-induced migration in peripheral blood cells in a dose-responsive manner. Selectivity testing against a panel of 7 transmembrane domain receptors indicated that BX 513 is inactive on a number of receptors at concentrations up to 10 μM [2].
In vivo: Currently, there is no animal in-vivo data available.
Clinical trial: Up to now, BX 513 is still in the preclinical development stage.
Reference:
[1] Ng HP,?May K,?Bauman JG,?Ghannam A,?Islam I,?Liang M,?Horuk R,?Hesselgesser J,?Snider RM,?Perez HD,?Morrissey MM.? Discovery of novel non-peptide CCR1 receptor antagonists. J Med Chem.?1999 Nov 4;42(22):4680-94.
[2] Hesselgesser J,?Ng HP,?Liang M,?Zheng W,?May K,?Bauman JG,?Monahan S,?Islam I,?Wei GP,?Ghannam A,?Taub DD,?Rosser M,?Snider RM,?Morrissey MM,Perez HD,?Horuk R.? Identification and characterization of small molecule functional antagonists of the CCR1 chemokine receptor. J Biol Chem.?1998 Jun 19;273(25):15687-92.
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