Safe and Efficient Sigma1 Ligand: A Potential Drug Candidate for Multiple Sclerosis
Abstract
:1. Introduction
2. Results
2.1. In Vitro Drug Candidate Assessment
2.1.1. Metabolic Stability and Metabolite Identification and Profiling
2.1.2. Preliminary ADME Studies
2.1.3. Safety Pharmacology and Toxicology
2.2. Evaluation of Compound 7i as a Sigma1 Receptor Agonist
2.3. In Vivo Pharmacology
2.3.1. Preliminary Pharmacokinetic Analysis
2.3.2. Effects of Systemic Administration of the Selective 7i Drug on the Cardiovascular System
2.4. In Vivo Efficacy of the Selective 7i Agonist in an MS Experimental Model
3. Discussion
4. Materials and Methods
4.1. Chemical
4.2. In Vitro Metabolic Stability and Metabolite Identification
4.3. Assay for Binding to Sigma Receptors
4.4. Physicochemical Properties, Absorption, Distribution and Toxicity
4.5. Toxicology
4.6. In Vitro Evaluation of S1R Functionality
4.7. In Vivo Evaluation of S1R Functionality
4.8. Phamacokinetic Analyses
4.9. Animals
4.10. Pro-Arrhythmic Effects
4.11. EAE Induction and Evaluation
4.12. Statistical Analysis
5. Patents
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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mLM | hLM | ||||||
---|---|---|---|---|---|---|---|
t1/2 (h) | CLint (µL/min/pmol) | Compound Remaining (1 h, %) | t1/2 (h) | CLint (µL/min/pmol) | Compound Remaining (1 h, %) | ||
7i | 1.2 | <115 | 54 | 1.9 | <115 | 66 | |
7i-deMe | 3.9 | <115 | 80 | 10.0 | <115 | 83 |
Ki | Inhibition | |||
---|---|---|---|---|
S1R (nM) | S2R (nM) | Ratio S2R/S1R | SH-SY5Y (% at 100 µM) | |
7i [28] | 3.2 | 190 | 60 | 28 |
7i-deMe | 23 | >1000 | >500 | 77 |
7i | 7i-deMe | |
---|---|---|
Solubility (µM) | ||
PBSpH7.4 | 185 | 187 |
SGF | 193 | 197 |
SIF | 188 | 196 |
Permeability (×10−6 cm/s) | ||
A/B pH6.5/7.4 | 29.1 | 31.1 |
B/A pH6.5/7.4 | 66.1 | 51.5 |
e-ratio | 2.3 | 1.7 |
Plasma t½ (h) | 25.9 | 23 |
PPB (%) | 94 | 81 |
CYPs inhibition (%) | ||
CYP1A | 2.1 | 9.4 |
CYP2B6 | −4.3 | 15.9 |
CYP2C8 | −9.2 | −7.2 |
CYP2C9 | −7.2 | 5.9 |
CYP2C19 | 36.5 | 18.4 |
CYP2D6 | 95.1 | 91.6 |
CYP3A | 36.9 | 3.2 |
Drug transporters inhibition (%) | ||
ABC family | ||
P-gp | 10.6 | 1.0 |
BCRP | 8.3 | −3.0 |
MRP1 | 1.9 | −3.4 |
MRP2 | −18.8 | −11.5 |
MRP3 | −0.3 | −0.6 |
SLC family | ||
OATP1B1 | 12.0 | 8.6 |
OATP1B3 | 23.1 | 19.1 |
OAT1 | −9.6 | −6.2 |
OAT3 | 34.3 | 18.7 |
OCT1 | 41.2 | 64.6 |
OCT2 | 49.4 | 85.8 |
ABST | 5.3 | 5.0 |
NTCP | −1.7 | 8.7 |
P-gp substrate (×10−6 cm/s) | ||
PBS (×10−6 cm/s) | ||
A/B pH7.4/7.4 | 45.8 | |
B/A pH7.4/7.4 | 11.7 | |
e-ratio | 0.3 | |
Verapamil (×10−6 cm/s) | ||
A/B pH7.4/7.4 | 28.0 | |
B/A pH7.4/7.4 | 16.9 | |
e-ratio | 0.6 | |
CYPs induction (%) | ||
CYP1A2 | ||
#1 (2) | 2.7 | |
#2 (5) | 1.5 | |
#3 (2) | 1.9 | |
CYP2B6 | ||
#1 (3) | 4.1 | |
#2 (4) | 4.1 | |
#3 (2) | 4.2 | |
CYP3A4 | ||
#1 (4) | 4.2 | |
#2 (6) | 1.6 | |
#3 (3) | 0.8 |
7i | |
---|---|
Cardiotoxicity | |
hERG inhibition (mM) | |
IC50 | 1 |
Cytotoxicity | |
HepG2 (% at 10 µM) | |
Cell number | −3 |
Intracell free calcium | 0 |
Nuclear size | 9 |
Membrane permeability | 0 |
Mitochondrial membrane potential | 5 |
TA1535 | TA1537 | TA98 | TA100 | TA102 | ||
---|---|---|---|---|---|---|
Dose (µg/plate) | −S9 | −S9 | −S9 | −S9 | −S9 | |
Positive control | (a) | 85.9 | 8.4 | 23.1 | 13.5 | 6.0 |
Vehicle control | 0 | - | - | - | - | - |
7i | 40 | 1.3 | 0.9 | 1.1 | 0.9 | 0.7 |
+S9 | +S9 | +S9 | +S9 | +S9 | ||
Positive control | (b) | 26.9 | 27.6 | 36.0 | 6.0 | 5.7 |
Vehicle control | 0 | - | - | - | - | - |
7i | 40 | 0.9 | 1.1 | 1.1 | 0.9 | 1.0 |
3 h Short Treatment With 24 h Recovery Period | 27 h Continuous Treatment | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
−S9 | +S9 | −S9 | ||||||||
µg/mL | RS (%) | MN/2 × 103 Cells | µg/mL | RS (%) | MN/2 × 103 Cells | µg/mL | RS (%) | MN/2 × 103 Cells | ||
Positive control | Mytomice C | 0.5 | 62.8 | 153.0 | 0.2 | 67.9 | 62.0 | |||
Griseofulvin | 5 | 70.5 | 63.0 | |||||||
Cyclophosphamide | 5 | 88.3 | 35.5 | |||||||
Vehicle control | 0 | - | 3.0 | 0 | - | 11.0 | 0 | - | 9.5 | |
7i | 275 | 80.0 | 8.0 | 275 | 103.7 | 9.0 | 275 | 70.1 | 6.0 | |
137.5 | 92.7 | 8.0 | 137.5 | 97.2 | 6.0 | 137.5 | 84.2 | 7.0 | ||
68.78 | 94.1 | 6.0 | 68.75 | 106.1 | 10.5 | 68.75 | 86.6 | 1.0 |
i.v | p.o | |
---|---|---|
Plasma | ||
tmax (min) | 0 | ≤30 |
Cmax (ng/mL) * | 180 | NA |
C30 (ng/mL) | 79.8 | 6.4 |
AUC t∞/AUC ∞ | 0.9 | 6.1 |
Vd (mL/kg) | 6.1 | 168.0 |
CLT (mL/min) | 3.8 | 74.9 |
t1/2 el (min) | 44.5 | 25.5 |
MAT (min) | 0 | 16.5 |
F (%) | 100 | 5 |
Brain | ||
tmax (min) | ≤30 | ≤30 |
C30 (ng/mL) | 234.3 | 20.7 |
AUC t∞/AUC ∞ | 5.9 | 7.6 |
CLbrain (mL/min) | 1.8 | 12.8 |
t1/2 el (min) | 96.4 | 78.9 |
D (%) | 61.7 | NA |
Brain/Plasma | 2.9 | 3.2 |
QT Interval | |||||||
---|---|---|---|---|---|---|---|
Time after Injection | |||||||
Dose (mg/kg) | Basal | 3 min | 6 min | 10 min | 20 min | 30 min | |
Vehicle | 51 ± 2 | 46 ± 3 | 45 ± 4 | 56 ± 9 | 62 ± 7 | 63 ± 11 | |
7i | 0.5 | 49 ± 3 | 48 ± 4 | 46 ± 4 | 53 ± 3 | 59 ± 4 | 58 ± 3 |
1.0 | 48 ± 1 | 45 ± 2 | 46 ± 2 | >49 ± 1 | > | ||
>5.0 | >46 ± 3 | >43 ± 1 | >42 ± 2 | >43 ± 2 | > | ||
10.0 | 46 ± 1 | 43 ± 1 | 45 ± 3 | 49 ± 2 | 52 ± 1 | 54 ± 1 | |
Quinidine | 10.0 | 46 ± 2 | 50 ± 2 | 64 ± 6 | 65 ± 5 * | ||
100.0 | 47 ± 4 | 58 ± 3 | 84 ± 7 * | 76 ± 4 * |
Product | Manufacturer | Reference Number |
---|---|---|
CD3 Antibody, anti-human APC-VIO® 770 | Miltenyi Biotec | 130-113-136 |
CD4 Antibody, anti-human PerCP-Vio® 700 | Miltenyi Biotec | 130-113-228 |
CD8 Antibody, anti-human VioGreen™ | Miltenyi Biotec | 130-110-684 |
CD25 Antibody, anti-human, Vio® Bright B515 | Miltenyi Biotec | 130-115-536 |
CD127 Antibody, anti-human, PE-Vio® 770 | Miltenyi Biotec | 130-113-415 130-113-412 |
CD19 Antibody, anti-human, PE-Vio® 615 | Miltenyi Biotec | 130-114-522 |
CD196 (CCR6) Antibody, anti-human, PE | Miltenyi Biotec | 130-120-458 |
FoxP3 Antibody, anti-human, APC | Miltenyi Biotec | 130-125-580 |
Viobility 405/452 Fixable Dye | Miltenyi Biotec | 130-110-205 |
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Oxombre, B.; Madouri, F.; Journé, A.-S.; Ravez, S.; Woitrain, E.; Odou, P.; Duhal, N.; Ninni, S.; Montaigne, D.; Delhem, N.; et al. Safe and Efficient Sigma1 Ligand: A Potential Drug Candidate for Multiple Sclerosis. Int. J. Mol. Sci. 2022, 23, 11893. https://doi.org/10.3390/ijms231911893
Oxombre B, Madouri F, Journé A-S, Ravez S, Woitrain E, Odou P, Duhal N, Ninni S, Montaigne D, Delhem N, et al. Safe and Efficient Sigma1 Ligand: A Potential Drug Candidate for Multiple Sclerosis. International Journal of Molecular Sciences. 2022; 23(19):11893. https://doi.org/10.3390/ijms231911893
Chicago/Turabian StyleOxombre, Bénédicte, Fahima Madouri, Anne-Sophie Journé, Séverine Ravez, Eloise Woitrain, Pascal Odou, Nathalie Duhal, Sandro Ninni, David Montaigne, Nadira Delhem, and et al. 2022. "Safe and Efficient Sigma1 Ligand: A Potential Drug Candidate for Multiple Sclerosis" International Journal of Molecular Sciences 23, no. 19: 11893. https://doi.org/10.3390/ijms231911893