p38α (IC50 < 1 μM)

Acumapimod/BCT197 is a p38α inhibitor with a lower than 1 μM IC50 value. BCT197 is an oral low‐molecular‐weight p38 inhibitor currently in development for the treatment of several inflammatory conditions, including COPD.[2]

Acumapimod (BCT-197) is an oral low-molecular-weight p38 inhibitor being developed for oral use to treat inflammatory conditions, such as chronic obstructive pulmonary disease (COPD) and other inflammatory diseases. Acumapimod (75 mg on days 1 and 6) is administered intermittently for a brief period of time and shows a significant improvement in lung function in COPD patients[2].

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When examining Acumapimod (BCT-197) in vivo, and comparing to vehicle-treated animals, reduced weight loss, improvement in survival and lack of impaired viral control was observed at Acumapimod (BCT-197) concentrations relevant to those being used in clinical trials of acute exacerbations of chronic obstructive pulmonary disease; at higher concentrations of BCT197 these effects were reduced. Conclusions: Compared to vehicle treatment, Acumapimod (BCT-197) (administered at a clinically relevant concentration) improved outcomes in a mouse model of influenza. This is encouraging given that the use of innate inflammatory pathway inhibitors may raise concerns of negative effects on infection regulation.https://pubmed.ncbi.nlm.nih.gov/29458547/

BCT197 inhibited TNFα secretion with an IC50 of 44 µg/L. Predose TNFα levels correlated with IC50 and were modeled as a covariate (ΔOBJ 17). Maximum inhibition from baseline was not complete but plateaued in the typical individual at about 66% (Imax).
In placebo‐treated subjects, nonstationarity in measurements of ex vivo LPS‐induced TNFα secretion was seen (Figure 2 c, inset). A circadian periodicity of shed TNFα receptors which attenuated response to LPS cannot be ruled out. Accordingly, drug effect was described as an inhibitory function on an oscillatory input system characterized by a physical frequency of 2π/24 hours (Eq. 1), and all available TNFα data of both BCT197 treated subjects and matching placebos were modeled simultaneously.[2]

Part 1 of study CBCT197A2101 was a randomized, double‐blind, placebo‐controlled, ascending single‐dose study to evaluate safety, tolerability, PK and PD of oral Acumapimod (BCT-197) in healthy subjects. Part 2 was a 14‐day, randomized, double‐blind, placebo‐controlled, ascending multiple dose study evaluating the PK and PD of oral Acumapimod (BCT-197). PD effect of BCT197 in Parts 1 and 2 was assessed by measuring TNFα levels in ex vivo LPS‐challenged blood samples. Details of the PK and PD sampling regimen, ex vivo LPS challenge, and bioanalysis of Acumapimod (BCT-197) and TNFα are provided in the Supplementary Methods. Part 3 of the study determined the effect of a single oral administration of BCT197 on serum TNFα levels after in vivo intravenous LPS challenge. Only PK data of this part were used, as it did not measure ex vivo LPS‐induced TNFα. Subjects fasted for 10 hours prior to Acumapimod (BCT-197) administration and continued to fast for 4 hours postdosing. No fluid intake apart from the fluid given at the time of drug intake was allowed from 2 hours before until 2 hours after dosing. Drug administrations were oral solutions with doses ranging from 0.1 to 3 mg, and tablets at doses of 5 mg and higher.[2]

Drug administrations were oral solutions with doses up to 3 mg, and tablets at doses of 5 mg and higher. The population PK parameters along with their unexplained BSV and relative standard errors (RSE) are summarized in Table 1. Acumapimod (BCT-197) was found to be a low clearance drug (1.76 L/h), with linearity in oral drug clearance (CL/F) demonstrated over the entire dose range tested (0.1–75 mg). No relevant differences in relative bioavailability between these formulations were seen. Acumapimod (BCT-197) exhibited an apparent absorption plateau, with a tendency to less than dose‐proportional increase in peak drug concentration (Cmax). For tablets, the mixed‐order absorption model consisted of a first‐order process (Kt = 1.12 h−1), absorbing a fraction (fc) of on average 66% of dose, and a parallel zero‐order process characterized by a Rate of 2,300 µg/h (Table 1 ). A mixed‐order absorption model was significantly better than zero‐order (ΔOFV −509) or first‐order absorption (ΔOFV −403). Model parameters Rate and fc were found to be independent of dose. Addition of a random effect on Rate or fc did not improve the model fit. Oral absorption from the solution was parsimoniously described using a first‐order process (Ks). Limited data in the absorption phase impaired accurate estimation of Ks.[2]

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Population predictions from linear disposition models showed overprediction in Cmax as well as underprediction in terminal disposition half‐life, particularly at low doses, despite dose linearity in CL/F. Conversely, the quasi‐equilibrium model with negligible receptor turnover from the peripheral compartment as depicted in Figure 2 captured well the apparent nonlinearity in tissue distribution (model equations in Supplementary Methods), and dropped the OFV by 123 points (Supplementary Table S2). The dissociation constant (Kd) and maximal binding (Bmax) were estimated to be respectively 367 µg and 500 µg. Limited‐capacity binding caused steady‐state volume of distribution (Vss/F) to increase with decreasing dose, with a limiting value of 132 L when the dose approached zero (Table 1). As expected, a competing quasi‐equilibrium model with nonlinear tissue binding into the central compartment showed bias in the structural model diagnostics (not shown).[2]

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Acumapimod (BCT-197) exhibited double peak behavior at about 18 to 24 hours postdose (Figure 1). This may indicate a late absorption window or drug redistribution by a shunt, possibly enterohepatic. The addition of a shunt feature further dropped OFV by 62 points. The full shunt model, however, was overparameterized (data too sparse). A reduction in degrees of freedom was achieved by fixing the duration of drug shunting (Tpump) as well as the rate of drug transfer from Ashunt into Aint (Db). Because model fit was insensitive to Kint1, it was set equal to Kt.[2]

Continuous dosing of Acumapimod (BCT-197) 10 mg resulted in dose‐limiting acneiform skin rashes, whereas the drug was found to be well tolerated at single high doses up to 75 mg (data not shown). This observation, in addition to tolerance, raised the question whether Acumapimod (BCT-197) would be most efficacious in a continuous or intermittent regimen. Although the translational value of the ex vivo TNFα bioassay remains to be shown, efforts were made to assess the impact of dosing schedule on drug response through use of simulation.[2]

[1]. Investigational p38 inhibitors for the treatment of chronic obstructive pulmonary disease. Expert Opin Investig Drugs. 2015 Mar;24(3):383-92.

[2]. Population PK-PD Model for Tolerance Evaluation to the p38 MAP Kinase Inhibitor BCT197. CPT Pharmacometrics Syst Pharmacol. 2015 Dec;4(12):691-700.

Acumapimod is under investigation in clinical trial NCT02926326 (The Effect of Azithromycin on BCT197 Exposure in Healthy Male Volunteers).

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Introduction: The JAK kinases are a family of four tyrosine receptor kinases that play a pivotal role in cytokine receptor signalling pathways via their interaction with signal transducers and activators of transcription proteins. Selective inhibitors of JAK kinases are viewed as of considerable potential as disease-modifying anti-inflammatory drugs for the treatment of rheumatoid arthritis. Areas covered: This article provides a review of the clinical development and available clinical results for those JAK inhibitors currently under investigation. Phase II data for four JAK inhibitors (baricitinib, decernotinib, filgotinib and INCB-039110) are contrasted with that reported for the recently approved JAK inhibitor tofacitinib. The preclinical data on these, in addition to peficitinib, ABT-494, INCB-047986 and AC-410 are also discussed, as are some of the inhibitors in preclinical development. Expert opinion: JAK inhibitors are effective in the treatment of rheumatoid arthritis as evidenced by several inhibitors enabling the majority of treated patients to achieve ACR20 responses, with baricitinib and INCB-039110 both effective when administered once daily. JAK inhibitors differ in isoform specificity profiles, with good efficacy achievable by selective inhibition of either JAK1 (filgotinib or INCB-039110) or JAK3 (decernotinib). It remains to be seen what selectivity provides the optimal side-effect profile and to what extent inhibition of JAK2 should be avoided. Keywords: JAK1 inhibitor; JAK3 inhibitor; baricitinib; decernotinib; filgotinib; peficitinib; rheumatoid arthritis; tofacitinib.[1]

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The p38 mitogen-activated protein kinase (p38) is a key signaling pathway involved in regulation of inflammatory cytokines. Unexpectedly, several clinical studies using p38 inhibitors found no convincing clinical efficacy in the treatment of chronic inflammation. It was the objective of this study to characterize the population pharmacokinetics (PK) of BCT197 in healthy volunteers and to examine the relationship between BCT197 exposure and pharmacodynamics (PD) measured as inhibition of ex vivo lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFα), a downstream marker of p38 activity. PK was characterized using a two-compartment model with mixed-order absorption and limited-capacity tissue binding. The PK-PD relationship revealed that suppression of TNFα was partly offset over time, despite continuous drug exposure. This may indicate a mechanism by which the inflammatory response acquires the ability to bypass p38. Simulations of posology dependence in drug effect suggest that an intermittent regimen may offer clinical benefit over continuous dosing and limit the impact of tolerance development.[2]

C22H19N5O2

385.42

385.153

C, 68.56; H, 4.97; N, 18.17; O, 8.30

836683-15-9

11338127

Yellow to orange solid powder

1.4±0.1 g/cm3

675.6±55.0 °C at 760 mmHg

362.4±31.5 °C

0.0±2.1 mmHg at 25°C

1.708

2.57

2

5

5

29

684

0

N#CC1C=C(C(C2=C(N)N(C3C(C)=CC=C(C(NC4CC4)=O)C=3)N=C2)=O)C=CC=1

VGUSQKZDZHAAEE-UHFFFAOYSA-N

InChI=1S/C22H19N5O2/c1-13-5-6-16(22(29)26-17-7-8-17)10-19(13)27-21(24)18(12-25-27)20(28)15-4-2-3-14(9-15)11-23/h2-6,9-10,12,17H,7-8,24H2,1H3,(H,26,29)

3-[5-amino-4-(3-cyanobenzoyl)pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.49 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 25.0 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: ≥ 2.5 mg/mL (6.49 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 25.0 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: ≥ 2.5 mg/mL (6.49 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 25.0 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.)