CCR5 ( IC50 = 3.6 nM ); CCR2 ( IC50 = 6.2 nM )
BMS-813160 is a dual antagonist of CCR2 and CCR5 receptors [1]

BMS-813160 acts as a potent and selective dual antagonist of CCR2 and CCR5 receptors, with the following binding IC₅₀ values: CCR2 Bnd IC₅₀ = 1.1±0.5 nM, CCR5 Bnd IC₅₀ = 23.6±12 nM; CCR2 Bnd IC₅₀ = 27±1.3 nM, CCR5 Bnd IC₅₀ = 6.3±1.5 nM [2]

BMS-813160 binds to CCR2, CCR5, CCR1, CCR4, and CXCR2 with IC50s of 6.2 nM, 3.6 nM, ＞25 μM, ＞40 μM and ＞40 μM, respectively[2].
MS-813160 exhibits activities to CCR2 CTX, CCR2 CD11b, CCR5 CTX, and CCR5 CD11b with IC50s of 0.8, 4.8, 1.1 and 5.7 nM, respectively[2].

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BMS-813160 is demonstrated to be a potent drug with good absorption and a good duration of action. It exhibits better properties compared to similar compounds previously claimed by Bristol-Myers Squibb [1]

In vitro experiments show that BMS-813160 has good permeability at pH = 7.4 in Parallel Artificial Membrane Permeability Assay (PAMPA) experiments. Additionally, it demonstrates excellent stability in human liver microsomes and exhibits potent, selective antagonistic activity against CCR2 and CCR5 receptors [2]

BMS-813160 (10-160 mg/kg; p.o. twice daily for two days) exhibits good oral bioavailability and prevents the migration of inflammatory monocytes and macrophages in a mouse model of thioglycollate-induced peritonitis[2].

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BMS-813160 was evaluated in the mouse thioglycollate-induced peritonitis model. The results confirmed its ability to inhibit the migration of inflammatory monocytes and macrophages [2]

Method for liver microsome t1/2 assay (LM t1/2). [2]
Using compound 3 as an example, compound 3 (0.5 M) was incubated with liver microsomes (1 mg/mL final concentration) fortified with NADPH (1 mM) at 37 °C. Metabolic reactions were terminated after 0, 5, 10, 15, 30, and 45 minutes by transferring an aliquot of the reaction mixtures into an acetonitrile quench solution to denature microsomal enzymes. The relative amount of the compound 3 remaining in the reaction mixtures at each time point was quantified using LC-MS/MS analysis. The results for each time point were normalized to the relative amount of compound 3 in the 0-minute sample and expressed as percent remaining. The elimination rate constant (kel) was determined using a linear regression model (natural logarithm of % remaining versus time), and metabolic half-life was calculated (0.693 /kel).

Human CXCR2 binding assay (CXCR2 Bnd).[2]
The human CXCR2 ligand binding assay was established with human overexpressed pEAK cells using human [ 125I]-Interlukin-8 as the tracer ligand. 10 μg of membrane per well was incubated with [125I]-Interleukin-8 (2000 Ci/mmol, 0.162 nM) and 200 nM unlabeled ligand in a total volume of 0.1 mL for 90 min at 25 °C. The mixture was filtered over GF/C (S&S) filters (presoaked in 0.5% PEI) and the filters were washed 5x with 1 mL ice-cold 50 mM HEPES-KOH (pH 7.4), 0.5 M NaCl and 0.1% BSA. After washing, the plate was air-dried for 60 minutes at room temperature. This was followed by adding 25 L of Microscint 20 into each well. The plate was sealed and counted on the S5 Trilux for 1 min. All conditions were tested in duplicate. The IC50 is defined as the concentration of competing cold ligand required to reduce specific binding by 50%.

Human-CCR2 knock-in C57BL/6 male mice with thioglycollate injection
10, 50 and 160 mg/kg
Oral gavage; 10-160 mg/kg twice a day; for two days

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Thioglycollate (TG)-induced peritonitis mouse model[2]
Six to eight C57BL/6 male mice (Taconic Laboratories), age 9-11 weeks, were treated with compound (vehicle was 0.02 N HCl) by gavage one hour prior to thioglycollate challenge. Thioglycollate (Hardy Diagnostics) was administered IP, 1 mL per mouse. For the 48 hour model, mice were dosed by gavage, BID, for 2 days. On day 3, serum was collected for compound exposure, and the mice were sacrificed by carbon dioxide overdose. The peritoneal cavity was injected with 5 mL phosphate-buffered saline containing 0.01M EDTA and 10% fetal bovine serum. The peritoneal cavity was massaged 15 times, and then the contents collected to retrieve the inflammatory cells. The typical retrieval volume was 4.2-4.5 mL. Total cell counts were determined on a CASY counter, and cytospin slides were made of the lavaged cells. The slides were stained with Diff-Quik, and differential cell counts were performed by manually counting 200 cells per slide. The total cell number of each inflammatory cell type was calculated for each mouse. The average and standard error of the mean (SEM) for recruited monocytes and macrophages for each group was plotted.

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For the evaluation of BMS-813160, the mouse thioglycollate-induced peritonitis model was used. The model was established by inducing peritonitis with thioglycollate, and the drug’s effect on the migration of inflammatory monocytes and macrophages was observed. Specific details such as drug dissolution formulation, administration frequency, and administration route were not described [2]

BMS-813160 has been reported to have good absorption [1]
Pharmacokinetic studies in dogs and cynomolgus monkeys have shown that BMS-813160 has excellent oral bioavailability and low clearance [2]

[1]. A dual CCR2/CCR5 chemokine antagonist, BMS-813160? Evaluation of WO2011046916. Expert Opin Ther Pat. 2011 Dec;21(12):1919-24.

[2]. BMS-813160: A Potent CCR2 and CCR5 Dual Antagonist Selected as a Clinical Candidate. ACS Med Chem Lett. 2021 Oct 15;12(11):1753-1758.

BMS-813160 is being investigated in the clinical trial NCT03496662 (BMS-813160 in combination with nivolumab, gemcitabine, and nab-paclitaxel for the treatment of borderline resectable and locally advanced pancreatic ductal adenocarcinoma (PDAC)). The CCR2/CCR5 antagonist BMS-813160 antagonizes human CC chemokine receptors type 2 (CCR2; CD192) and type 5 (CCR5; CD195), exhibiting potential immunomodulatory and antitumor activity. Upon administration, the CCR2/CCR5 antagonist BMS-813160 specifically binds to and blocks the activation of CCR2 and CCR5. This inhibits CCR2/CCR5-mediated signal transduction pathways and may suppress inflammatory processes, angiogenesis, tumor cell migration, tumor cell proliferation, and invasion. G protein-coupled chemokine receptors CCR2 and CCR5 are expressed on the surface of monocytes and macrophages, stimulating their migration and invasion; they play a crucial role in inflammation and autoimmune diseases. CCR2 and CCR5 are overexpressed in certain cancer cell types and are also involved in angiogenesis and the migration, proliferation, and metastasis of tumor cells. The patent application related to BMS-813160 claims protection for the crystalline form N-1 of the compound (chemical name: (S)-1-[(1S,2R,4R)-4-isopropyl(methyl)amino)-2-propylcyclohexyl]-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidine-2-one), its preparation method, and its therapeutic use. BMS-813160 has been identified as a candidate drug for clinical development[1]

BMS-813160 (referred to as compound 3 in this paper) exists in two conformations: conformation A and conformation B. This paper provides the synthetic route of BMS-813160 (scheme 1), with the following key reaction steps and conditions: (a) reaction with EtO₂C-NCS in EtOAc and benzene, yield 90%; (b) reaction with NaOH, yield 95%; (c) reaction with Ra-Ni and NH₄OH in MeOH at 100 °C, yield 50%; (d) reaction with POCl₃ under heating conditions (Δ); (e) reaction with compound 9 and Et₃N in iPrOH, yield 15%. Due to its favorable pharmacological and pharmacokinetic properties, BMS-813160 was selected as a clinical candidate drug [2].

C25H40N8O2

484.637504577637

484.33

C, 61.96; H, 8.32; N, 23.12; O, 6.60

1286279-29-5

51039119

White to off-white solid powder

2.7

3

7

7

35

778

4

CC(=O)N[C@@H]1C[C@@H](CC[C@@H]1N2CC[C@@H](C2=O)NC3=NC=NC4=CC(=NN43)C(C)(C)C)NC(C)(C)C

CMVHFGNTABZQJU-HCXYKTFWSA-N

InChI=1S/C25H40N8O2/c1-15(34)28-18-12-16(30-25(5,6)7)8-9-19(18)32-11-10-17(22(32)35)29-23-27-14-26-21-13-20(24(2,3)4)31-33(21)23/h13-14,16-19,30H,8-12H2,1-7H3,(H,28,34)(H,26,27,29)/t16-,17+,18-,19+/m1/s1

N-[(1R,2S,5R)-5-(tert-butylamino)-2-[(3S)-3-[(7-tert-butylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino]-2-oxopyrrolidin-1-yl]cyclohexyl]acetamide

BMS813160; BMS-813160; BMS 813160 - Bio-X; BMS813160; BMS 813160; 83U7957287; Acetamide, N-((1R,2S,5R)-5-((1,1-dimethylethyl)amino)-2-((3S)-3-((7-(1,1-dimethylethyl)pyrazolo(1,5-a)-1,3,5-triazin-4-yl)amino)-2-oxo-1-pyrrolidinyl)cyclohexyl)-; N-((1R,2S,5R)-5-((1,1-Dimethylethyl)amino)-2-((3S)-3-((7-(1,1-dimethylethyl)pyrazolo(1,5-a)-1,3,5-triazin-4-yl)amino)-2-oxo-1-pyrrolidinyl)cyclohexyl)acetamide; BMS 813160

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 25~97 mg/mL (51.6~200.1 mM)
Ethanol: ~97 mg/mL

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.29 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.29 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.29 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)