CCR1 antagonist | BI 639667

Target protein: 
CCR1
Probe Name: 
BI 639667
MOLECULAR WEIGHT [DA]: 
451.5
In stock: 
534

Chemical structure

2D structure of BI-9667

Highlights

BI 639667 is a potent and selective antagonist to human CCR1, including in the whole blood setting. Its rodent cross-reactivity is limited. The compound shows good physico-chemical and pharmacokinetic properties. It is projected to have a human half-life of 9-12 h. It was targeted to be dosed once-a-day to achieve IC90 coverage at trough levels of the human whole blood assay IC50. No pre-clinical safety liabilities have been identified (CV safety, drug-drug interaction potential, rodent and dog toxicology).

3D structure of BI-9667

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Target information

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)

Complex of human CCR2 with orthosteric and allosteric antagonists (PDB code: 5t1a)

In vitro Activity

BI 639667 is a potent human CCR1 antagonist (Human whole blood receptor internalization IC50 9 nM)

In vitro activity table

Probe name / Negative control

BI 639667

BI-9307

MW [Da]

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.

In vitro DMPK parameters

In vitro DMPK parameters table

Probe name / Negative control

BI 639667

BI-9307

Solubility @ pH 6.8 [µg/ml]

7

>65
(unknown crystallinity)

CACO permeability @ pH 7.4 [*10-6 cm/s]

2.9

n.d.

CACO efflux ratio

7.3

n.d.

Human hepatocyte clearance [%QH]

<5

33 (HLM)

Plasma protein binding human

66%

n.d.

In vivo DMPK parameters

In vivo DMPK parameters table

BI 639667

Rat

Dog

Cyno

CL [%QH]

13

5.8

17

MRT [h]

1.9

6.9

4.4

Vss [L/kg]

1.1

0.7

1.9

F

10%

29%

35%

In vivo pharmacology

Due to reduced 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

Negative control

MOLECULAR WEIGHT OF NEGATIVE CONTROL [DA]: 
546.6

A structurally closely related inactive analogue, BI-9307, is available.

BI-9307, negative control

BI-9307, negative control

Selectivity

Good selectivity. Eurofins-Panlabs® receptor screen on 69 targets @ 10 µM: 67 targets < 45% inhibition, A2A/HU: 69%, DATRANS 71%; neither reproduced in dose response

Selectivity data available

Probe name

BI 639667

Cerep®

No

Eurofins-Panlabs®

Yes

Invitrogen®

No

DiscoverX®

No

Dundee

No

Download selectivity data: 

reference molecules

CCX-354, BMS-817399

Summary

BI 639667 is a potent, selective human CCR1 antagonist with optimized drug-like properties.

Supplementary data

References

  1. Chemokine blockade and chronic inflammatory disease: proof of concept in patients with rheumatoid arthritis

    . Haringman, J. J.; Kraan, M. C.; Smeets, T. J. M.; Zwinderman, K. H.; Tak, P. P.

    Ann. Rheum. Dis. 2003;62:715-721.

  2. 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.

  3. 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.