Format

Send to

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

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

Author information

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.

Abstract

The discovery and selection of a highly potent and selective NaV1.7 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

PMID:
29029933
DOI:
10.1016/j.bmcl.2017.09.056
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center