Background/Purpose:  Chemokines are key regulators of leukocyte activation and recruitment to sites of inflammation. Of particular relevance in rheumatoid arthritis (RA), the chemokine receptors CCR1 and CCR6 are thought to drive monocyte/macrophage and Th17 cell recruitment, respectively, into RA joints. We recently demonstrated the clinical benefit of our first-generation CCR1 antagonist (CCX354) in a Phase 2 trial in RA patients (Tak (2012)). Meanwhile, CCR6 is thought to be a key factor for Th17 cell activity in RA and psoriasis. To date, no therapeutic agents targeting CCR6 have progressed into clinical evaluation. Our objective is to identify orally active small molecules that selectively target either CCR1 or CCR6 and possess overall profiles suitable for clinical development.

Methods: The in vitro potency of CCX9588 (CCR1 antagonist) was assessed by inhibition of CCL15-mediated chemotaxis of THP-1 cells and human blood monocytes. The in vitropotency of CCX9664 (CCR6 antagonist) was assessed by inhibition of CCL20-mediated chemotaxis and binding using CCR6-expressing cell lines and CD4-positive human PBMC. CCX9588 and CCX9664 were assessed for their ability to block CCR1 or CCR6-mediated chemotaxis towards RA synovial fluids. The ability of a CCR6 antagonist to inhibit dermal inflammation in preclinical models of psoriasis-like disease was assessed in mice with the imiquimod and IL-23 models.

Results: CCX9588 potently blocks CCR1-mediated chemotaxis with an IC₅₀ of 0.1 nM (THP-1 cells). In 100% human serum, CCX9588 blocks CCR1-mediated chemotaxis with an IC₅₀ of 0.7 nM (THP-1 cells) and 0.2 nM (human monocytes). CCX9588 also completely blocks the monocyte-chemotactic activity displayed by human RA synovial fluid samples. CCX9664 potently blocks CCR6-mediated chemotaxis of CD4-positive human PBMC (IC₅₀: 24 nM). CCR6-mediated chemotactic activity of RA synovial samples was completely inhibited by CCR6 antagonists. CCX9664 significantly reduced dermal manifestations of disease in two preclinical psoriasis-like models, one induced by topical application of imiquimod and the other by dermal injections of IL-23. Both CCX9588 and CCX9664 are highly selective for CCR1 and CCR6, respectively, when tested against a wide screen of chemokine and chemoattractant receptors.

Conclusion:

CCR1: The novel second-generation CCR1 antagonist CCX9588 is about 20 times more potent on human CCR1 than the structurally distinct first-generation molecule CCX354. This new CCR1 antagonist (CCX9588) remains equally selective for CCR1 and orally bioavailable in preclinical species (Dairaghi (2011)) and was shown to block CCR1-mediated chemotaxis of human blood monocytes towards RA synovial fluid samples.

CCR6: Several chemical lead series were identified using a proprietary high-throughput screening format. Optimization of one of these series resulted in advanced molecules such as CCX9664. This molecule is highly potent on human and mouse CCR6 and displays properties conducive to its use for the treatment of diseases such as RA and psoriasis.

References: (a) Dairaghi, D. et al. (2011) Clin. Pharmacol. Ther., 89(5): 726; (b) Tak, P.P. et al. (2013) Ann. Rheum. Dis.,72(3): 337.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inhibition-of-chemokine-receptors-ccr1-and-ccr6-as-promising-therapies-for-autoimmune-diseases-such-as-rheumatoid-arthritis-and-psoriasis/