Table 5. BRS-3 Potency, Selectivity,a and Pharmacokineticb Profile of 22 (MK-5046).
| human | mouse | rat | dog | rhesus | |
|---|---|---|---|---|---|
| BRS3 IC50 (nM) | 28 ± 13 | 5.4 ± 2 | 1.2 ± 0.4 | 6.5 ± 1.9 | 50 ± 15 |
| BRS3 Ki (nM) | 3.7 ± 0.5 | 1.6 ± 0.7 | 0.6 ± 0.2 | 9.9 ± 1.3 | 2.4 ± 1.3 |
| BRS3 EC50 (nM) | 14 ± 4 | 21 ± 0.9 | 2.2 ± 1 | 1.6 ± 0.8 | 6.9 ± 4 |
| % activationc | 100 ± 6 | 120 ± 10 | 110 ± 9 | 100 ± 58 | 110 ± 8 |
| NMBR IC50 (nM) | >10000 | ||||
| GRPR IC50 (nM) | >10000 | ||||
| hERG Ki (μM) | >8 | ||||
| DLZ IC50 (μM) | 1.9 | ||||
| hPXR EC50 (μM) | >25 | ||||
| po AUCN [μM h/(mg/kg)] | 0.1 | 1.2 | 3.7 | 0.8 | |
| Foral (%) | 9.6 | 64 | 52 | 18 | |
| Clp (mL/min/kg) | 32 | 20 | 5.6 | 8.8 | |
| Vdss (L/kg) | 2.2 | 0.98 | 0.45 | 0.44 | |
| T1/2 (h) | 1.1 | 0.7 | 1.4 | 1.0 |
a
Data expressed as means ± SDs (≥3 independent experiments) or single value.
b
Plasma clearance (Clp), volume of distribution (Vdss), and half-life (T1/2) calculated following 1 mg/kg iv dose in mouse and rat and 0.5 mg/kg iv dose in dog and rhesus. Oral bioavailability (Foral) calculated following 2 mg/kg in mouse and rat and 1 mg/kg in dog and rhesus.
c
% activation represents the maximum activation of tested compounds relative to that of dY-peptide for human, dog, and rhesus receptors and a reference small molecule BRS-3 agonist for mouse and rat receptors.