Highly potent and selective NaV1.7 inhibitors for use as intravenous agents and chemical probes

R Ian Storer; Andy Pike; Nigel A Swain; Aristos J Alexandrou; Bruce M Bechle; David C Blakemore; Alan D Brown; Neil A Castle; Matthew S Corbett; Neil J Flanagan; David Fengas; M Scott Johnson; Lyn H Jones; Brian E Marron; C Elizabeth Payne; David Printzenhoff; David J Rawson; Colin R Rose; Thomas Ryckmans; Jianmin Sun; Jonathan W Theile; Rubben Torella; Elaine Tseng; Joseph S Warmus

doi:10.1016/j.bmcl.2017.09.056

Highly potent and selective Na_V1.7 inhibitors for use as intravenous agents and chemical probes

Bioorg Med Chem Lett. 2017 Nov 1;27(21):4805-4811. doi: 10.1016/j.bmcl.2017.09.056. Epub 2017 Sep 28.

Authors

R Ian Storer¹, Andy Pike², Nigel A Swain³, Aristos J Alexandrou⁴, Bruce M Bechle⁵, David C Blakemore³, Alan D Brown³, Neil A Castle⁶, Matthew S Corbett⁵, Neil J Flanagan⁷, David Fengas⁸, M Scott Johnson⁶, Lyn H Jones⁹, Brian E Marron⁶, C Elizabeth Payne⁴, David Printzenhoff⁶, David J Rawson¹⁰, Colin R Rose⁵, Thomas Ryckmans¹⁰, Jianmin Sun⁵, Jonathan W Theile⁶, Rubben Torella³, Elaine Tseng¹¹, Joseph S Warmus⁵

Affiliations

¹ Worldwide Medicinal Chemistry, Pfizer Ltd, The Portway, Granta Park, Cambridge CB21 6GS, UK. Electronic address: ian.storer@astrazeneca.com.
² Pharmacokinetics, Dynamics and Metabolism, Pfizer Ltd, The Portway, Granta Park, Cambridge CB21 6GS, UK.
³ Worldwide Medicinal Chemistry, Pfizer Ltd, The Portway, Granta Park, Cambridge CB21 6GS, UK.
⁴ Electrophysiology, Pfizer Ltd, The Portway, Granta Park, Cambridge CB21 6GS, UK.
⁵ Worldwide Medicinal Chemistry, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
⁶ Icagen Inc, 4222 Emperor Blvd #350, Durham, NC 27703, USA.
⁷ Pharmaceutical Sciences, Pfizer Ltd, The Portway, Granta Park, Cambridge CB21 6GS, UK.
⁸ Peakdale Molecular, Ltd, Discovery Park House, Ramsgate Road, Sandwich, Kent CT13 9ND, UK.
⁹ Worldwide Medicinal Chemistry, Pfizer Inc, 610 Main Street, Cambridge, MA 02139, USA.
¹⁰ Worldwide Medicinal Chemistry, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK.
¹¹ Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Eastern Point Road, Groton, CT 06340, USA.

PMID: 29029933
DOI: 10.1016/j.bmcl.2017.09.056

Abstract

The discovery and selection of a highly potent and selective Na_V1.7 inhibitor PF-06456384, designed specifically for intravenous infusion, is disclosed. Extensive in vitro pharmacology and ADME profiling followed by in vivo preclinical PK and efficacy model data are discussed. A proposed protein-ligand binding mode for this compound is also provided to rationalise the high levels of potency and selectivity over inhibition of related sodium channels. To further support the proposed binding mode, potent conjugates are described which illustrate the potential for development of chemical probes to enable further target evaluation.

Keywords: Acid isostere; Ion channel; Pain; Voltage-gated.

MeSH terms

Animals
Binding Sites
Dogs
Half-Life
Hepatocytes / metabolism
Humans
Infusions, Intravenous
Inhibitory Concentration 50
Mice
Microsomes, Liver / metabolism
Molecular Docking Simulation
NAV1.7 Voltage-Gated Sodium Channel / chemistry*
NAV1.7 Voltage-Gated Sodium Channel / metabolism
Pain / drug therapy
Pain / pathology
Piperidines / chemistry*
Piperidines / pharmacokinetics
Piperidines / therapeutic use
Protein Binding
Protein Structure, Tertiary
Pyridines / chemistry*
Pyridines / pharmacokinetics
Pyridines / therapeutic use
Rats
Structure-Activity Relationship
Sulfonamides / chemistry*
Sulfonamides / pharmacokinetics
Sulfonamides / therapeutic use
Thiadiazoles
Voltage-Gated Sodium Channel Blockers / chemistry*
Voltage-Gated Sodium Channel Blockers / pharmacokinetics
Voltage-Gated Sodium Channel Blockers / therapeutic use

Substances

NAV1.7 Voltage-Gated Sodium Channel
PF-06456384
Piperidines
Pyridines
Sulfonamides
Thiadiazoles
Voltage-Gated Sodium Channel Blockers