CCR1 antagonist
BI 639667
BI-639667 is a potent and selective antagonist to the human chemokine receptor CCR1. It has been tested in the whole blood setting but not in in vivo disease models due to limited rodent cross-reactivity. The compound shows good physicochemical and PK properties, with a projected human half-life of 9-12 h. No pre-clinical safety liabilities have been identified (CV safety, drug-drug interaction potential, rodent toxicology). It was targeted once-a-day dosing to achieve IC50 coverage at trough levels of the human whole blood.
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Chemotactic cytokine receptor-1 (CCR1) is a G protein-coupled receptor that belongs to a family of more than 20 chemokine receptors that have emerged as attractive targets for drug discovery. There are various chemokines that interact with these chemokine receptors and are well known to mediate basal and inflammatory leukocyte trafficking. CCR1 is expressed on immune cell types including monocytes, macrophages, T-lymphocytes, neutrophils, basophils, eosinophils, NK cells, mast cells and dendritic cells. The binding of the chemokine MIP-1 alpha (CCL3), MCP3 (CCL7) and RANTES (CCL5) to CCR1 is reported to play a role in the trafficking of monocytes, macrophages and Th1 cells to inflamed tissues in rheumatoid arthritis (RA) and multiple sclerosis (MS). Macrophages and Th1 cells in the synovia of RA patients are also major producers of MIP-1 alpha and RANTES, and they continuously recruit leukocytes to the synovial tissues of RA patients resulting in chronic inflammation. Thus, CCR1 has been regarded as a potential target for treating inflammatory disease. Antagonists that block the interactions between CCR1 and its chemokine ligands could block chemotaxis of monocytes, macrophages and Th1 cells to inflamed tissues ameliorating the chronic inflammation associated with autoimmune diseases such as RA and MS. However, in 2013, it was demonstrated by BMS that with sufficiently target coverage no significant efficacy was achieved in a Phase IIa RA trial. Consequently, development of BI 639667 was halted also.
Complex of human CCR2 with orthosteric and allosteric antagonists (PDB code: 5t1a)
| Probe name / negative control | BI 639667 | BI-9307 |
| MW [Da]a | 451.5 | 546.6 |
| CCR1 binding affinity (IC50) [nM] (SPA binding) | 5.4 | n.d. |
| CCR1 molecular potency (IC50) [nM] (Ca flux) | 24 | >3000 |
| CCR1 cellular potency (IC50) [nM] (chemotaxis) | 2.4 | n.d. |
| Whole blood potency (IC50) [nM] (Receptor internalization) | 9 | n.d. |
aFor the salt form you will get, please refer to the label on the vial and for the molecular weight of the salt, please refer to the FAQs
| Probe name / negative control | BI 639667 | BI-9307 |
| logD @ pH11 | 2.0 | 1.5 |
| Solubility @ pH 6.8 [µg/mL] | 15.9 | >65 |
| Caco-2 permeability AB @ pH 7.4 [*10-6 cm/s] | 2.9 | n.a. |
| CACO efflux ratio | 18 | n.a. |
| Human hepatocyte clearance [% QH] | <21 | 33 (HLM) |
| Plasma Protein Binding human | 66 | n.a. |
| BI 639667 | Rat | Dog | Cyno |
| Clearance [% QH]a | 13 | 5.8 | 17 |
| Mean residence time after i.v. dose [h] | 1.9 | 6.9 | 4.4 |
| Vss [L/kg] | 1.1 | 0.7 | 1.9 |
| F [%] | 10 | 29 | 35 |
ai.v. dose: 1mg/kg
Due to reduced mouse rodent potency this compound was not tested in in vivo disease models. However, efficacy in models such as collagen induced arthritis (CIA) in mouse has been demonstrated with cross-reactive tool compound in house.
A structurally closely related inactive analogue, BI-9307, is available.
BI-9307, negative control
Good selectivity. Eurofins Safety Panel 44™ receptor screen on 69 targets @ 10 µM: 67 targets < 45% inhibition, A2A/HU: 69%, DATRANS 71%; neither reproduced in dose response
| SELECTIVITY DATA AVILABLE | BI-639667 | BI-9307 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| PDSP4 | Yes | Yes |
| Invitrogen® | No | No |
| DiscoverX® | No | No |
| Dundee | No | No |
Download selectivity data:
BI-639667_selectivityData.xlsx
BI-9307_selectivityData.xlsx
CCX-354, BMS-817399
CCR1 is a key chemokine receptor for human monocyte/macrophage chemotaxis. BI 639667 blocks influx of pro-inflammatory cells to the site of inflammation.
Chemokine Receptor CCR1 antagonist CCX-354-C treatment for Rheumatoid Arthritis: CARAT-2, a Randomised, Placebo controlled Clinical Trial.
Tak P. P., Balanescu A., Tseluyko V., Bojin S., Drescher E., Dairaghi D., Miao S., Marchesin V., Jaen J., Schall T. J., Bekker P.
Ann. Rheum. Dis. 2013, 72, 337-344.
THU0109 Lack of Efficacy of CCR1 Antagonist BMS-817399 in Patients with Moderate to Severe Rheumatoid Arthritis: Results of 12-Week Proof-of-Concept Study EULAR 2014 Poster
Kivitz A., Maciag P., Gulati P., Shuyan D., Connolly S. E., Davies P., Li X., Repsher T., Haggerty H. G., Londei M.
When you plan a publication, please use the following acknowledgement:
BI 639667 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.