Table 1.
Characterization of Lu AF21934, Lu AF21935 and Lu AF32615
| Lu AF21934 (1) | Lu AF21935 (2) | Lu AF32615 (3) | ||
|---|---|---|---|---|
| Human mGlu4 receptor PAM EC50 | nM | 500 | >10 000 | 910 |
| %Modulation (EMAX) | % | 120 | 18 | 170 |
| Glutamate fold shift | – | 5 | – | 10 |
| Molecular weight | Amu | 315.2 | 315.2 | 197.2 |
| cLogP | – | 3.3 | 3.3 | 2.4 |
| LogD7.4 | – | 3.3 | 3.3 | n/a |
| tPSA | Å2 | 72.2 | 72.2 | 51.8 |
| Kinetic solubility pH 7.4 | μM | 120 | 120 | 170 |
| Optical rotation | [α]21D | +45c | −39c | Achiral |
| PAMPA PAPP | 10−6 cm·s−1 | 7 | 7 | 24 |
| MDCK PAPP | A→B; B→A, Ratio | 44; 30; 0.7 | n/a | 42; 28; 0.7 |
| rPPB | % | 95.6 | 87.6 | 88.3 |
| Rat brain unbound fraction UBBR | % | 3.0 | 1.9 | 1.9 |
| Rat CLint | mL·min−1 | 13 | 77 | 11 |
| Brain | ng·g−1 | 2422b | 740b | 822d |
| Plasma | ng·mL−1 | 2763b | 840b | 350d |
| Brain/Plasma ratio | – | 0.9b | 0.9ab | 2.3d |
| CSF | ng·mL−1 | 95b | 42b | n/a |
| mGlu receptor selectivity | FLIPR screens at 10 μM | mGlu6 receptor PAM; EC50 = 7 μM | No significant cross reactivity at 10 μM | Not active at mGlu1,2,3,5,7 in PAM, NAM and agonist mode at 10 μM |
| Broad cross reactivity panel | Binding inhibition | A2A antagonist Ki = 7 μM; 5-HT2B antagonist Ki = 2 μM | No significant cross reactivity at 10 μM | No significant cross reactivity at 10 μM |
a, Data for Lu AF21934 partly reported in Bennouar et al. (2013); b, Rat, SC dosing at 10 mg·kg−1, 1 h post-dose, formulated in 20% aqueous HPBCD; c, MeOH/CH2Cl2 (1:1); 2 mg·mL−1; d, PO, 10 mg·kg−1, 1 h post-dose, same formulation as b.