PF-05089771 | PF-5089771 | CAS#1235403-62-9 | Nav1.7 Inhibitor

MedKoo Cat#: 530305 | Name: PF-05089771

Description:

WARNING: This product is for research use only, not for human or veterinary use.

PF-05089771 is a Selective Nav1.7 Inhibitor (IC50 = 11 nM) that interacts with the voltage-sensor domain (VSD) of domain IV. PF-05089771 exhibits a slow onset of block that is depolarization and concentration dependent, with a similarly slow recovery from block. Human hereditary gain- or loss-of-pain disorders have demonstrated an essential role of Nav1.7 sodium channels in the sensation of pain, thus making this channel an attractive target for new pain therapies.

Chemical Structure

PF-05089771

CAS#1235403-62-9 (free base)

Theoretical Analysis

MedKoo Cat#: 530305

Name: PF-05089771

CAS#: 1235403-62-9 (free base)

Chemical Formula: C18H12Cl2FN5O3S2

Exact Mass: 498.9743

Molecular Weight: 500.34

Elemental Analysis: C, 43.21; H, 2.42; Cl, 14.17; F, 3.80; N, 14.00; O, 9.59; S, 12.82

Price and Availability

Size	Price	Availability
50mg	USD 550.00	2 Weeks
100mg	USD 950.00	2 Weeks
200mg	USD 1,650.00	2 Weeks
500mg	USD 2,850.00	2 Weeks
1g	USD 3,750.00	2 Weeks
2g	USD 6,250.00	2 Weeks

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Related CAS #

1235403-62-9 (free base) 1430806-04-4 (tosylate)

Synonym

F-05089771; PF 05089771; PF05089771; PF-5089771; PF5089771; PF 5089771.

IUPAC/Chemical Name

4-(2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

InChi Key

ZYSCOUXLBXGGIM-UHFFFAOYSA-N

InChi Code

InChI=1S/C18H12Cl2FN5O3S2/c19-9-1-2-14(10(3-9)11-6-24-25-18(11)22)29-15-5-13(21)16(4-12(15)20)31(27,28)26-17-7-30-8-23-17/h1-8,26H,(H3,22,24,25)

SMILES Code

O=S(C1=CC(Cl)=C(OC2=CC=C(Cl)C=C2C3=C(N)NN=C3)C=C1F)(NC4=CSC=N4)=O

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Instruction

View handling instruction

Biological target:

PF 05089771 is a potent, orally active and selective arylsulfonamide Nav1.7 inhibitor, with IC50 values of 11 nM, 12 nM, 13 nM, 171 nM and 8 nM for hNav1.7, cynNav1.7, dogNav1.7, ratNav1.7, and musNav1.7.

In vitro activity:

This study further characterized the state-dependent interaction of PF-05089771 by systematically varying the voltage, frequency, and duration of conditioning prepulses to provide access to closed, open, and fast- or slow-inactivated states. The current study demonstrates that PF-05089771 exhibits a slow onset of block that is depolarization and concentration dependent, with a similarly slow recovery from block. Furthermore, the onset of block by PF-05089771 develops with similar rates using protocols that bias channels into predominantly fast- or slow-inactivated states, suggesting that channel inhibition is less dependent on the availability of a particular inactivated state than the relative time that the channel is depolarized. Reference: Mol Pharmacol. 2016 Nov;90(5):540-548. https://pubmed.ncbi.nlm.nih.gov/27587537/

In vivo activity:

This study evaluated the antitussive effect of NaV1.7 blocker PF-05089771 administered systemically and topically in awake guinea pigs using capsaicin cough challenge. Compared to vehicle, peroral or inhaled PF-05089771 administration caused about 50-60 % inhibition of cough at the doses that did not alter respiratory rate. This study concludes that the NaV1.7 blocker PF-05089771 inhibits cough in a manner consistent with its electrophysiological effect on airway C-fibre nerve terminals. Reference: Respir Physiol Neurobiol. 2022 May;299:103856. https://pubmed.ncbi.nlm.nih.gov/35114369/

	Solvent	mg/mL	mM	comments
Solubility
	DMSO	100.0	199.86

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 500.34 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Matthews RM, Bradley E, Griffin CS, Lim XR, Mullins ND, Hollywood MA, Lundy FT, McGarvey LP, Sergeant GP, Thornbury KD. Functional expression of NaV1.7 channels in freshly dispersed mouse bronchial smooth muscle cells. Am J Physiol Cell Physiol. 2022 Sep 1;323(3):C749-C762. doi: 10.1152/ajpcell.00011.2022. Epub 2022 Jul 25. PMID: 35876287. 2. Theile JW, Fuller MD, Chapman ML. The Selective Nav1.7 Inhibitor, PF-05089771, Interacts Equivalently with Fast and Slow Inactivated Nav1.7 Channels. Mol Pharmacol. 2016 Nov;90(5):540-548. doi: 10.1124/mol.116.105437. Epub 2016 Sep 1. PMID: 27587537. 3. Brozmanova M, Buday T, Konarska M, Plevkova J. The effect of the voltage-gated sodium channel NaV1.7 blocker PF-05089771 on cough in the guinea pig. Respir Physiol Neurobiol. 2022 May;299:103856. doi: 10.1016/j.resp.2022.103856. Epub 2022 Jan 31. PMID: 35114369.

In vitro protocol:

In vivo protocol:

1. Brozmanova M, Buday T, Konarska M, Plevkova J. The effect of the voltage-gated sodium channel NaV1.7 blocker PF-05089771 on cough in the guinea pig. Respir Physiol Neurobiol. 2022 May;299:103856. doi: 10.1016/j.resp.2022.103856. Epub 2022 Jan 31. PMID: 35114369.

1: Kim JS, Meeker S, Ru F, Tran M, Zabka TS, Hackos D, Undem BJ. Role of NaV1.7 in postganglionic sympathetic nerve function in human and guinea-pig arteries. J Physiol. 2024 Jul;602(14):3505-3518. doi: 10.1113/JP286538. Epub 2024 May 14. PMID: 38743485; PMCID: PMC11250678. 2: Xie YF, Yang J, Ratté S, Prescott SA. Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs. Elife. 2024 Apr 30;12:RP90960. doi: 10.7554/eLife.90960. PMID: 38687187; PMCID: PMC11060714. 3: Nair SS, Pavelkova N, Murphy CM, Kollarik M, Taylor-Clark TE. Action potential conduction in the mouse and rat vagus nerve is dependent on multiple voltage-gated sodium channels (NaV1s). J Neurophysiol. 2023 Sep 1;130(3):684-693. doi: 10.1152/jn.00041.2023. Epub 2023 Aug 16. PMID: 37584077; PMCID: PMC10635471. 4: Deng L, Dourado M, Reese RM, Huang K, Shields SD, Stark KL, Maksymetz J, Lin H, Kaminker JS, Jung M, Foreman O, Tao J, Ngu H, Joseph V, Roose-Girma M, Tam L, Lardell S, Orrhult LS, Karila P, Allard J, Hackos DH. Nav1.7 is essential for nociceptor action potentials in the mouse in a manner independent of endogenous opioids. Neuron. 2023 Sep 6;111(17):2642-2659.e13. doi: 10.1016/j.neuron.2023.05.024. Epub 2023 Jun 22. PMID: 37352856. 5: Fu Y, Sun L, Zhu F, Xia W, Wen T, Xia R, Yu X, Xu D, Peng C. Ectopic expression of Nav1.7 in spinal dorsal horn neurons induced by NGF contributes to neuropathic pain in a mouse spinal cord injury model. Front Mol Neurosci. 2023 Mar 3;16:1091096. doi: 10.3389/fnmol.2023.1091096. PMID: 36937049; PMCID: PMC10020601. 6: Brozmanova M, Buday T, Jakusova J, Melegova J, Plevkova J. Influence of combined voltage-gated sodium channel NaV1.7 and NaV1.8 inhibitors on cough in a guinea pig model. Respir Physiol Neurobiol. 2023 Jun;312:104043. doi: 10.1016/j.resp.2023.104043. Epub 2023 Mar 5. PMID: 36871863. 7: Matthews RM, Bradley E, Griffin CS, Lim XR, Mullins ND, Hollywood MA, Lundy FT, McGarvey LP, Sergeant GP, Thornbury KD. Functional expression of NaV1.7 channels in freshly dispersed mouse bronchial smooth muscle cells. Am J Physiol Cell Physiol. 2022 Sep 1;323(3):C749-C762. doi: 10.1152/ajpcell.00011.2022. Epub 2022 Jul 25. PMID: 35876287. 8: Alles SRA, Smith PA. Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets. Front Pain Res (Lausanne). 2021 Dec 13;2:750583. doi: 10.3389/fpain.2021.750583. PMID: 35295464; PMCID: PMC8915663. 9: Li S, Ding M, Wu Y, Xue S, Ji Y, Zhang P, Zhang Z, Cao Z, Zhang F. Histamine Sensitization of the Voltage-Gated Sodium Channel Nav1.7 Contributes to Histaminergic Itch in Mice. ACS Chem Neurosci. 2022 Mar 2;13(5):700-710. doi: 10.1021/acschemneuro.2c00012. Epub 2022 Feb 14. PMID: 35157443. 10: Brozmanova M, Buday T, Konarska M, Plevkova J. The effect of the voltage- gated sodium channel NaV1.7 blocker PF-05089771 on cough in the guinea pig. Respir Physiol Neurobiol. 2022 May;299:103856. doi: 10.1016/j.resp.2022.103856. Epub 2022 Jan 31. PMID: 35114369. 11: Lim XR, Bradley E, Griffin CS, Hollywood MA, Sergeant GP, Thornbury KD. Fast voltage-dependent sodium (NaV ) currents are functionally expressed in mouse corpus cavernosum smooth muscle cells. Br J Pharmacol. 2022 Mar;179(5):1082-1101. doi: 10.1111/bph.15728. Epub 2021 Dec 16. PMID: 34767251. 12: Kollarik M, Ru F, Pavelkova N, Mulcahy J, Hunter J, Undem BJ. Role of NaV 1.7 in action potential conduction along human bronchial vagal afferent C-fibres. Br J Pharmacol. 2022 Jan;179(2):242-251. doi: 10.1111/bph.15686. Epub 2021 Nov 8. PMID: 34634134. 13: Hadley S, Patil MJ, Pavelkova N, Kollarik M, Taylor-Clark TE. Contribution of tetrodotoxin-sensitive, voltage-gated sodium channels (NaV1) to action potential discharge from mouse esophageal tension mechanoreceptors. Am J Physiol Regul Integr Comp Physiol. 2021 Nov 1;321(5):R672-R686. doi: 10.1152/ajpregu.00199.2021. Epub 2021 Sep 15. PMID: 34523364; PMCID: PMC8616622. 14: Pavelkova N, Brozmanova M, Jayanta Patil M, Kollarik M. Voltage-gated sodium channels mediating conduction in vagal motor fibers innervating the esophageal striated muscle. Physiol Res. 2020 Dec 31;69(Suppl 3):S471-S478. doi: 10.33549/physiolres.934600. PMID: 33476169; PMCID: PMC8603713. 15: Ru F, Pavelkova N, Krajewski JL, McDermott JS, Undem BJ, Kollarik M. Stimulus intensity-dependent recruitment of NaV1 subunits in action potential initiation in nerve terminals of vagal C-fibers innervating the esophagus. Am J Physiol Gastrointest Liver Physiol. 2020 Oct 1;319(4):G443-G453. doi: 10.1152/ajpgi.00122.2019. Epub 2020 Jul 29. PMID: 32726130; PMCID: PMC7654645. 16: Jo S, Bean BP. Lidocaine Binding Enhances Inhibition of Nav1.7 Channels by the Sulfonamide PF-05089771. Mol Pharmacol. 2020 Jun;97(6):377-383. doi: 10.1124/mol.119.118380. Epub 2020 Mar 19. PMID: 32193331; PMCID: PMC7237866. 17: Siebenga P, van Amerongen G, Hay JL, McDonnell A, Gorman D, Butt R, Groeneveld GJ. Lack of Detection of the Analgesic Properties of PF-05089771, a Selective Nav 1.7 Inhibitor, Using a Battery of Pain Models in Healthy Subjects. Clin Transl Sci. 2020 Mar;13(2):318-324. doi: 10.1111/cts.12712. Epub 2019 Nov 12. PMID: 31642607; PMCID: PMC7070789. 18: Liu J, Tan H, Yang W, Yao S, Hong L. The voltage-gated sodium channel Nav1.7 associated with endometrial cancer. J Cancer. 2019 Aug 27;10(20):4954-4960. doi: 10.7150/jca.31544. PMID: 31598168; PMCID: PMC6775510. 19: McDonnell A, Collins S, Ali Z, Iavarone L, Surujbally R, Kirby S, Butt RP. Efficacy of the Nav1.7 blocker PF-05089771 in a randomised, placebo-controlled, double-blind clinical study in subjects with painful diabetic peripheral neuropathy. Pain. 2018 Aug;159(8):1465-1476. doi: 10.1097/j.pain.0000000000001227. PMID: 29578944. 20: Chernov-Rogan T, Li T, Lu G, Verschoof H, Khakh K, Jones SW, Beresini MH, Liu C, Ortwine DF, McKerrall SJ, Hackos DH, Sutherlin D, Cohen CJ, Chen J. Mechanism-specific assay design facilitates the discovery of Nav1.7-selective inhibitors. Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E792-E801. doi: 10.1073/pnas.1713701115. Epub 2018 Jan 8. PMID: 29311306; PMCID: PMC5789920.

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BMS-946030

MedKoo CAT#: 145559

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