PF-00446687 (free base)

PF-00446687 is a potent, selective melanocortin-4 receptor (MC4R) agonist with EC50 of 12 ± 1 nM^[1]. Pf-446687 is brain penetrant^[2]. IC50 & Target:EC50: 12 ± 1 nM (MC4R)^[1] In Vitro: PF-00446687 binds MC4 receptor with a K_i of 27±4 nM. PF-00446687 has a relatively weak activity at the MC1, MC3, and MC5 receptors with EC₅₀s of 1.02±0.30 μM, 1.16±0.35 μM, and 1.98±0.20 μM, respectively. The broad off-target profiles of PF-00446687 are assessed in the CEREP Bioprint wide ligand screening panel, with the most potent binding activities being at the σ receptor (K_i=330 nM), the sodium ion channel (K_i=690 nM), and the muscarinic M2 receptor (K_i=730 nM)^[1]. In Vivo: Pf-446687 is highly selective for MC4R and is both brain penetrant and stable in vivo. Peripheral administration of the brain penetrant MC3/4R receptor peptide agonist, Melanotan II (MTII), and the highly selective, small molecule MC4R agonist, Pf-446687, enhances partner preference formation in the prairie vole, but not in the non-monogamous meadow vole^[2].