VU6028418 is a potent, highly selective and orally bioavailable M4 mAChR antagonist with an IC50 of 4.1 nM against hM4[1].
VU6028418 is orally bioavailable[1].
In Vivo PK Parameters for VU6028418[1]
| parameter | rat (SD)a | mouse (CD-1)a | dog (beagle)a |
| dose (mg/kg) iv/po | 1/10 | 1/3 | 1/3 |
| CLp (mL/min/kg) | 6.1 | 17 | 43 |
| Vss (L/kg) | 6.7 | 10.6 | 8.5 |
| elimination t1/2 (h) | 13 | NC | 15 |
| Cmax (ng/mL) po | 17 000 | 181 | 70 |
| Tmax (h) po | 1.5 | 6.67 | 17 |
| AUC0-inf (ng/mL•h) po | 30 000 | NC | 1100 |
| F (%) po | ≥100 | ≥100 | 86 |
| total brain/total plasma (Kp) | 6.4 | ND | ND |
| unbound brain/unbound plasma (Kp,uu) | 0.61 | ND | ND |
| CSF/plasma unbound (Kp,u) | 0.24 | ND | ND |
a Values represent means from two to three animals. ND = not determined. NC = not calculated; there was insufficient data to define the elimination phase (i.e., Cmax was one of the last three time points).
| Animal Model: | SD rat, CD-1 mouse and beagle dog[1] |
| Dosage: | 1, 3 and 10 mg/kg |
| Administration: | Intravenous injection or oral administration (Pharmacokinetic Analysis) |
| Result: | Showed good pharmacokinetic results. |
[1]. Spock M, et al. Discovery of VU6028418: A Highly Selective and Orally Bioavailable M4 Muscarinic Acetylcholine Receptor Antagonist. ACS Med Chem Lett. 2021 Aug 2;12(8):1342-1349.