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.

Identification of the Binding Site for a Novel Class of CCR2b Chemokine Receptor Antagonists

“…Because both classes of inhibitors are extremely weak binders to other chemokine receptors, including CXCR1, CCR1, and CCR3. Small molecular weight ligands for CCR1 and CXCR4 have been described (41)(42)(43); these compounds have no affinity for CCR2, findings that we have corroborated. 2 None of the CCR1 or CXCR4 antagonists similar structurally to either the SP or CP classes.…”

Targeting CCR1

“…The first were a novel series of 4-hydroxypiperidines that were discovered by high-throughput screening assays and which potently inhibited the binding of CCL3 and CCL5 to recombinant human CCR1 [47][48][49]. The initial HTS lead were optimized synthetically to yield a series of highly potent receptor antagonists exemplified by BX 510 and BX 513 [47][48][49] (compounds 1 and 2) that had K i values of 21 nM and 40 nM for CCR1 respectively, but unfortunately crossreacted with a number of other GPCRs, including adenosine A 3 , adrenergic-a 2A , dopamine D 2 , and muscarinic M 1 and M 2 (at K i values between 2 and 8 mM) thus precluding any further development [47]. The crossreactivity of BX 513 with biogenic amine neurotransmitter receptors [47], was not surprising for a structure reminiscent of a typical neuroleptic or antidepressant structural motif [50].…”

“…This antagonist is a substituted pyridylbenzoxepine of a series previously described by this group (compound 5) [73,74] and optimized from a tricyclic nonspecific CCR1 antagonist originally described by Berlex researchers (compound 1) [47,48]. It demonstrated high affinity binding for CCR1 (K i 1.2 nM) and had an IC 50 of 3.4 nM for the inhibition of chemotaxis induced by CCL3.…”

Structure Function Differences in Nonpeptide CCR1 Antagonists for Human and Mouse CCR1

“…The structure-activity relationships for one of these classes of compounds, the 4-hydroxypiperidines, has been well described for human CCR1 (9). During the optimization of these compounds we discovered that the lead candidate from this series, which was highly potent and had a binding affinity of 40 nM on human CCR1, was relatively ineffective in the mouse (10).…”

“…In this study we have further characterized the pharmacological basis for the species selectivity of these compounds by carrying out detailed structure function studies using our previous wide array of human CCR1 antagonists (9). These detailed studies have allowed us to identify a series of CCR1 antagonists displaying species selectivity for mouse and human CCR1 and to rationalize this selectivity based on compound structure.…”