Purity: > 98%
PF-05241328(cas 1387633-03-5) is a potent and selective inhibitor of Human Nav1.7 Voltage-Dependent Sodium Channel. PF-05089771 provided the best opportunity to explore Nav1.7 blockade for the treatment of acute or chronic pain conditions.
1. Clin Pharmacokinet. 2016 Jul;55(7):875-887. doi: 10.1007/s40262-015-0365-0.
Clinical Micro-Dose Studies to Explore the Human Pharmacokinetics of Four Selective Inhibitors of Human Nav1.7 Voltage-Dependent Sodium Channels.
Jones HM(1), Butt RP(2), Webster RW(1), Gurrell I(1), Dzygiel P(1), Flanagan N(3), Fraier D(1), Hay T(1), Iavarone LE(4), Luckwell J(1), Pearce H(3), Phipps A(4), Segelbacher J(1), Speed B(1), Beaumont K(1).
(1)Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide R&D, Sandwich, Kent, UK. (2)Neuroscience and Pain Research Unit, Pfizer Worldwide R&D, Granta Park, Cambridge, CB21 6GS, UK. email@example.com. (3)Department of Pharmaceutical Sciences, Pfizer Worldwide R&D, Sandwich, Kent, UK. (4)Clinical Pharmacology, Pfizer Worldwide R&D, Sandwich, Kent, UK.
BACKGROUND: The emergence of genetic data linking Nav1.7 sodium channel over- and under- expression to human pain signalling has led to an interest in the treatment of chronic pain through inhibition of Nav1.7 channels. OBJECTIVE: We describe the pharmacokinetic (PK) results of a clinical microdose study performed with four potent and selective Nav1.7 inhibitors and the subsequent modelling resulting in the selection of a single compound to explore Nav1.7 pharmacology at higher doses.
METHODS: A clinical microdose study to investigate the intravenous and oral PK of four compounds (PF-05089771, PF-05150122, PF-05186462 and PF-05241328) was performed in healthy volunteers. PK parameters were derived via noncompartmental analysis. A physiologically-based PK (PBPK) model was used to predict exposure and multiples of Nav1.7 50 % inhibitory concentration (IC50) for each compound at higher doses.
RESULTS: Plasma clearance, volume of distribution and bioavailability ranged from 45 to 392 mL/min/kg, 13 to 36 L/kg and 38 to 110 %, respectively. The PBPK model for PF-05089771 predicted a 1 g oral dose would be required to achieve exposures of approximately 12× Nav1.7 IC50 at maximum concentration (C max), and approximately 3× IC50 after 12 h (minimum concentration [C min] for a twice-daily regimen). Lower multiples of Nav1.7 IC50 were predicted with the same oral doses of PF-05150122, PF-05186462, and PF-05241328. In a subsequent single ascending oral dose clinical study, the predictions for PF-05089771 compared well with observed data.
CONCLUSION: Based on the human PK data obtained from the microdose study and subsequent modelling, PF-05089771 provided the best opportunity to explore Nav1.7 blockade for the treatment of acute or chronic pain conditions.