2-Aminopyridines As Potent and Selective Na1.8 Inhibitors Exhibiting Efficacy in a Nonhuman Primate Pain Model

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Jun 19

PMID 38894930

Authors

Michael J Breslin

Jeffrey W Schubert

Deping Wang

ChienJung Huang

Michelle K Clements

Yuxing Li

Xiaoping Zhou

Joshua D Vardigan

Richard L Kraus

Vincent P Santarelli

Jason M Uslaner

Paul J Coleman

Shawn J Stachel

Affiliations

Soon will be listed here.

Abstract

Herein we describe the discovery of a 2-aminopyridine scaffold as a potent and isoform selective inhibitor of the Na1.8 sodium channel. Parallel library synthesis, guided by predictions, rapidly transformed initial hits into a novel 2-aminopyridine lead class possessing good ADME and pharmacokinetic profiles that were able to display activity in a clinically translatable nonhuman primate capsaicin-sensitized thermode pharmacodynamic assay. Progress toward the lead identification, optimization, and efficacy of these compounds will be discussed.

References

Hijma H, Siebenga P, de Kam M, Groeneveld G . A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Pharmacodynamic Effects of VX-150, a Highly Selective NaV1.8 Inhibitor, in Healthy Male Adults. Pain Med. 2021; 22(8):1814-1826. PMC: 8346919. DOI: 10.1093/pm/pnab032. View

Ma R, Kayani K, Whyte-Oshodi D, Whyte-Oshodi A, Nachiappan N, Gnanarajah S . Voltage gated sodium channels as therapeutic targets for chronic pain. J Pain Res. 2019; 12:2709-2722. PMC: 6743634. DOI: 10.2147/JPR.S207610. View

Bagal S, Marron B, Owen R, Storer R, Swain N . Voltage gated sodium channels as drug discovery targets. Channels (Austin). 2015; 9(6):360-6. PMC: 4850042. DOI: 10.1080/19336950.2015.1079674. View

Vardigan J, Houghton A, Lange H, Adarayan E, Pall P, Ballard J . Pharmacological validation of a novel nonhuman primate measure of thermal responsivity with utility for predicting analgesic effects. J Pain Res. 2018; 11:735-741. PMC: 5903490. DOI: 10.2147/JPR.S152879. View

Gold M, Reichling D, Shuster M, Levine J . Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current in nociceptors. Proc Natl Acad Sci U S A. 1996; 93(3):1108-12. PMC: 40039. DOI: 10.1073/pnas.93.3.1108. View

Sangameswaran L, Delgado S, Fish L, Koch B, Jakeman L, Stewart G . Structure and function of a novel voltage-gated, tetrodotoxin-resistant sodium channel specific to sensory neurons. J Biol Chem. 1996; 271(11):5953-6. DOI: 10.1074/jbc.271.11.5953. View

Emery E, Luiz A, Wood J . Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief. Expert Opin Ther Targets. 2016; 20(8):975-83. PMC: 4950419. DOI: 10.1517/14728222.2016.1162295. View

Dib-Hajj S, Ishikawa K, Cummins T, Waxman S . Insertion of a SNS-specific tetrapeptide in S3-S4 linker of D4 accelerates recovery from inactivation of skeletal muscle voltage-gated Na channel mu1 in HEK293 cells. FEBS Lett. 1997; 416(1):11-4. DOI: 10.1016/s0014-5793(97)01154-x. View

Hijma H, van Brummelen E, Siebenga P, Groeneveld G . A phase I, randomized, double-blind, placebo-controlled, single- and multiple dose escalation study evaluating the safety, pharmacokinetics and pharmacodynamics of VX-128, a highly selective Na 1.8 inhibitor, in healthy adults. Clin Transl Sci. 2021; 15(4):981-993. PMC: 9010276. DOI: 10.1111/cts.13215. View

10.

Shah P, Westwell A . The role of fluorine in medicinal chemistry. J Enzyme Inhib Med Chem. 2007; 22(5):527-40. DOI: 10.1080/14756360701425014. View

11.

Leeson P, Springthorpe B . The influence of drug-like concepts on decision-making in medicinal chemistry. Nat Rev Drug Discov. 2007; 6(11):881-90. DOI: 10.1038/nrd2445. View

12.

Lai J, Gold M, Kim C, Bian D, Ossipov M, Hunter J . Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain. 2002; 95(1-2):143-52. DOI: 10.1016/s0304-3959(01)00391-8. View

13.

Levinson S, Luo S, Henry M . The role of sodium channels in chronic pain. Muscle Nerve. 2012; 46(2):155-65. PMC: 3400058. DOI: 10.1002/mus.23314. View

14.

Faber C, Lauria G, Merkies I, Cheng X, Han C, Ahn H . Gain-of-function Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci U S A. 2012; 109(47):19444-9. PMC: 3511073. DOI: 10.1073/pnas.1216080109. View

15.

Akopian A, Souslova V, England S, Okuse K, Ogata N, Ure J . The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci. 1999; 2(6):541-8. DOI: 10.1038/9195. View

16.

Cortinez L, Hsu Y, Sum-Ping S, Young C, Keifer J, Macleod D . Dexmedetomidine pharmacodynamics: Part II: Crossover comparison of the analgesic effect of dexmedetomidine and remifentanil in healthy volunteers. Anesthesiology. 2004; 101(5):1077-83. DOI: 10.1097/00000542-200411000-00006. View

17.

Benyamin R, Trescot A, Datta S, Buenaventura R, Adlaka R, Sehgal N . Opioid complications and side effects. Pain Physician. 2008; 11(2 Suppl):S105-20. View

18.

Bagal S, Bungay P, Denton S, Gibson K, Glossop M, Hay T . Discovery and Optimization of Selective Nav1.8 Modulator Series That Demonstrate Efficacy in Preclinical Models of Pain. ACS Med Chem Lett. 2015; 6(6):650-4. PMC: 4468395. DOI: 10.1021/acsmedchemlett.5b00059. View

19.

Vierck C, Wong F, King C, Mauderli A, Schmidt S, Riley 3rd J . Characteristics of sensitization associated with chronic pain conditions. Clin J Pain. 2013; 30(2):119-28. PMC: 4389646. DOI: 10.1097/AJP.0b013e318287aac7. View

20.

Petersen K, Rowbotham M . A new human experimental pain model: the heat/capsaicin sensitization model. Neuroreport. 1999; 10(7):1511-6. DOI: 10.1097/00001756-199905140-00022. View