Article Figures & Data
Figures
- Fig. 1.
Relationship between exposure and receptor occupancy across multiple mGlu5 NAM chemotypes. (A) Exposure plotted as plasma Cmax. (B) Exposure plotted as unbound plasma Cmax divided by the affinity (Ki) of each ligand at the mGlu5 receptor. The dotted line represents the theoretical curve fit where 50% occupancy is achieved when the unbound plasma = Ki. (C) Exposure plotted as the unbound brain concentration divided by the affinity (Ki) of each ligand at the mGlu5 receptor. The dotted line represents the theoretical curve fit where 50% occupancy is achieved when the unbound brain = Ki. Data were also fitted to a four-parameter sigmoidal dose-response curve (solid line). Cyno = cynomolgus monkey.
- Fig. 2.
Predicted vs. measured mGlu5 receptor occupancy of HTL0014242 across species. Comparison between the predicted (pred.) receptor occupancy (open icons) unbound plasma exposure vs. the measured (meas.) receptor occupancy (filled icons), demonstrating that plasma levels underpredict RO.
Tables
- TABLE 1
mGlu5 NAM inhibitor properties
cLogP, partition coefficient; Fup, free fraction in plasma; t1/2, half life; N/A, not available; Fubr, free fraction in brain
Identifier Dipraglurant Mavoglurant Basimglurant HTL0014242 Structure 
cLogP 2.58 3.16 4.71 3.04 mGlu5 pKi (means ± S.D.) Human 6.98 ± 0.24 7.95 ± 0.24 9.25 ± 0.40 9.30 ± 0.24 Monkey N/A N/A N/A 8.88 (n = 2) (8.71–9.05) Rat 7.21 (n = 2) (7.20–7.22) 8.07 ± 0.16 8.93 (n = 2) (8.81–9.06) 9.19 ± 0.11 Mouse 7.13 ± 0.11 7.89 ± 0.42 N/A 9.29 ± 0.18 Human plasma t1/2 (h) 0.68–0.75a 12 day 49–107b N/A Rat Fup 0.037 0.15 0.021c 0.0028 Fubr 0.13d 0.03d N/A 0.0019 Kp brain/plasma 0.11 1.6 1.7c 1.9 Kpuu 0.39 0.32 1.0c 1.3 - TABLE 2
Measured mGlu5 receptor occupancy and associated exposure dosing for HTL0014242. PK, pharmacokinetics; cyno, cynomolgus monkey; N/A, not available
Study Oral Dose Ligand for RO N RO mGlu5 RO Means ± S.D. Satellite n for PK Plasma Means ± S.D. Total Brain Means ± S.D. mg/kg % ng/ml Mouse ex vivo 2 [3H]M-MPEP 5 42 ± 15 From RO animals 26 ± 9.03 50 ± 20.2 Rat ex vivo 1 5 69 From RO animals 78.6 ± 47.0 101 ± 37.7 3 5 80 139 ± 22.8 162 ± 44.1 10 5 91 652 ± 229 753 ± 219 Mouse in vivo 1 2 12 (0, 24.7) 3 9.3a 34a 3 2 73 (64, 83) 3 28 ± 9.38 102 ± 34.5 10 2 88 (79, 96) 3 160 ± 50.5 419 ± 166 1b 3 24 ± 2.4 3 13 ± 11.7 100 ± 75.2 3b 3 77 ± 13 3 120 ± 9.82 243 ± 39.6 10b 3 95 ± 3.1 3 300 ± 42.2 577 ± 107 Rat PET studyc 1 [18F]FPEB 5 75 From RO animals 70.1 ± 30.7 225 ± 98.8 10 5 85 207 ± 77.9 666 ± 251 Cyno PET studyc 0.7 1 65 From RO animals 45 N/A 4 1 93 238 N/A Compound/Species Oral Dose Ligand for RO mGlu5 RO Means ± S.D. Plasma Means ± S.D. Brain Means ± S.D. Rat: mg/kg
Human: mg% ng/ml ng/ml Mavoglurant/rata 3 [3H]M-MPEP 45 ± 4 128 ± 64.2 204 ± 78.5 10 73 ± 2 466 ± 178.4 641 ± 178.4 30 83 ± 3 1002 ± 612.7 1505 ± 234.8 Basimglurant/rat N/A [3H]ABP688 50b 4.8b 8.2c Basimglurant/human 0.5 [11C]RO511232c 25d 4.20e 7.2f 1.5 53d 12.1e 20.5f Dipraglurant/human 100 [18F]FPEB 27 ± 9.0g 1586h 174i 200 44 ± 23g 3172h 349i 300 54 ± 30g 4758h 523i ↵a Values calculated from measured concentration (micromoles) presented in Bennett et al. (2014).
↵b Quoted EC50 (Lindemann et al., 2015).
↵c Estimated based on Kp 1.7 (Lindemann et al., 2015).
↵d Quoted at Css (Quiroz et al., 2016; PET study clinical trials.gov NCT01483469).
↵e Estimated from day 1 concentration (Cosson et al., 2018) taking account of accumulation to Css.
↵f Estimated at Css, assuming same brain partitioning as for rat.
↵g Addex Therapeutics Initiating Report Life Science Capital July 19, 2016.
↵h From normalizing day 1 50 mg human plasma Cmax reported (793 ng/ml) Tison et al. (2016). Data consistent with reported plasma EC50 2910 ± 152 ng/ml (Wong et al., 2018).
↵i Brain estimated assuming same brain partitioning as measured in the rat (Kp 0.11).
- TABLE 4
Measured and predicted mGlu5 RO for HTL0014242.ub, unbound; cyno, cynomolgus monkey; N/A, not available
Study Dose mGlu5 RO Measured mGlu5 RO Predicted from [Plasma]ub mGlu5 RO Predicted from [Brain]ub Measured RO: Predicted RO from Braina mg/kg % % Mouse ex vivo 2 42 ± 15 16 19 23 Rat ex vivo 1 69 52 49 20 3 80 66 61 19 10 91 90 88 3.0 Mouse in vivo 1 12 6.4 14 −2.0 3 73 17 33 41 10 88 54 66 22 1, i.p. 24 ± 2.4 8.7 32 −8 3, i.p. 77 ± 13 47 54 23 10, i.p. 95 ± 3.1 69 73 22 Rat PET study 1 75 49 66 8 10 85 74 87 −2 Cyno PET study 0.7 65 36 N/A N/A 4 93 75 N/A N/A ↵a Average RO underprediction ± S.D. 14% ± 14%.
- TABLE 5
Measured and predicted mGlu5 RO for mavoglurant, dipraglurant, and basimglurant. ub, unbound
Compound Species Dose mGlu5 RO Measured mGlu5 RO Predicted from [plasma]ub mGlu5 RO Predicted from [brain]ub Rat: mg/kg
Human: mg% Mavoglurant Rat 3 45 ± 4 85 64 10 73 ± 2 95 86 30 83 ± 3 98 95 Basimglurant Rat N/A 50a 41 36 Human 0.5 25 27 30 1.5 53 51 56 Dipraglurant Human 100 27 ± 9 66 43 200 44 ± 23 80 60 300 54 ± 30 85 69 ↵a Quoted EC50 (Lindemann et al., 2015).
