Pilavapadin

Pilavapadin

CAS1815613-42-3

MFC19H23F4N3O MW 385.4 g/mol

(2S)-1-{[2′,6-bis(difluoromethyl)[2,4′-bipyridin]-5-yl]oxy}-2,4-dimethylpentan-2-amine

(2S)-1-[[2-(difluoromethyl)-6-[2-(difluoromethyl)-4-pyridinyl]-3-pyridinyl]oxy]-2,4-dimethylpentan-2-amine
adaptor protein 2-associated kinase 1 (AAK1) inhibitor, LX9211, BMS-986176, LX 9211,  BMS 986176, Phase 2, Neuropathic pain, Postherpetic neuralgia, AAK1-IN-1, 9G4RLM5X6Z

Pilavapadin (also known as LX9211 or BMS-986176) is an investigational, orally available small molecule developed by Lexicon Pharmaceuticals for the treatment of neuropathic pain, primarily diabetic peripheral neuropathic pain (DPNP). 

Key Information

• Mechanism of Action: Pilavapadin is a selective inhibitor of AAK1 (AP2 associated kinase 1), a novel target identified through Lexicon’s gene science research. It is designed to inhibit the reuptake and recycling of neurotransmitters involved in pain signaling in the central nervous system without affecting opiate pathways.
• Indication: It is being investigated for the management of chronic and debilitating conditions such as diabetic peripheral neuropathic pain (DPNP), chemotherapy-induced peripheral neuropathy (CIPN), and multiple sclerosis (MS) pain.
• Development Stage: Pilavapadin has completed Phase 2 clinical trials for DPNP and is expected to advance to a Phase 3 trial.
• Status/Designation: The U.S. Food and Drug Administration (FDA) has granted Fast Track designation for the development of pilavapadin in DPNP. 

Clinical Trial Results

Phase 2 studies (RELIEF-DPN-1 and PROGRESS) demonstrated that pilavapadin can provide meaningful pain reduction in adults with DPNP. 

• In a post-hoc analysis of the PROGRESS study, the 10 mg dose was found to be effective, achieving a clinically meaningful, two-point reduction in average daily pain scores from baseline, with an acceptable safety and tolerability profile.
• The data has been presented at several medical meetings, including the European Association for the Study of Diabetes (EASD). 

• OriginatorBristol-Myers Squibb; Lexicon Pharmaceuticals
• DeveloperLexicon Pharmaceuticals
• ClassAnalgesics; Small molecules
• Mechanism of ActionAdaptor-associated kinase 1 inhibitors
• Phase IINeuropathic pain; Postherpetic neuralgia
• 20 Jun 2025Updated efficacy data from the phase II PROGRESS trial in Neuropathic pain presented at 85th Annual Scientific Sessions of the American Diabetes Association (ADA-2025)
• 13 May 2025Lexicon Pharmaceuticals plans an End of Phase 2 meeting with FDA for Pilavapadin
• 13 May 2025Updated efficacy data from the phase II PROGRESS trial in Neuropathic pain released by Lexicon Pharmaceuticals

• A Dose-ranging Study in Patients With Diabetic Peripheral Neuropathic Pain (DPNP)CTID: NCT06203002Phase: Phase 2Status: CompletedDate: 2025-08-29
• Efficacy, Safety, and PK of LX9211 in Participants With Diabetic Peripheral Neuropathic PainCTID: NCT04455633Phase: Phase 2Status: CompletedDate: 2025-06-25
• Efficacy and Safety of LX9211 in Participants With Postherpetic NeuralgiaCTID: NCT04662281Phase: Phase 2Status: CompletedDate: 2023-11-18

Molecular FormulaC₁₉H₂₃F₄N₃O.H₃O₄P

Molecular Weight483.4

CAS 2977251-24-2

SYN

US10155760,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US215884039&_cid=P11-MI4ESM-19570-1

Example 123

(S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

Part A: (2-(difluoromethyl)pyridin-4-yl)boronic acid

To a 20 mL vial was added 4-chloro-2-(difluoromethyl)pyridine hydrochloride (180 mg, 0.900 mmol), hypodiboric acid (121 mg, 1.350 mmol), 2-(dicyclohexylphosphino))-2′,4′,6′-triisopropylbiphenyl (8.58 mg, 0.018 mmol), Xphos precatalyst (7.08 mg, 9.00 μmol) and potassium acetate (265 mg, 2.70 mmol) in ethanol (8.5 mL) to give a tan suspension (degassed before adding agents). The bottle was capped and heated at 80° C. for 1.5 h. LCMS showed the consumption of the starting material and formation of a new spot: (2-(difluoromethyl)pyridin-4-yl)boronic acid. The mixture was divided into parts and directly used in the next step of different reactions.

Part B: (S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine

To a 5 mL vial was added (2-(difluoromethyl)pyridin-4-yl)boronic acid (25.9 mg, 0.15 mmol) was added potassium phosphate tribasic (1 mL, 0.500 mmol). After degassing for 5 min, Xphos precatalyst (4 mg, 5.08 μmol) and (S)-1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine (26.5 mg, 0.079 mmol) and tetrahydrofuran (1 mL) were added. The vial was sealed and heated at 80° C. overnight for 18 h. Volatiles were blown off. The residue was partitioned between EtOAc and water. The organic layer was dried, filtered and concentrated. The residue was dissolved in MeOH and purified by prep-HPLC to afford (S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (29.8 mg, 98%) as a colorless solid. 1H NMR (500 MHz, DMSO-d 6) δ 8.79 (d, J=5.2 Hz, 1H), 8.40 (d, J=8.8 Hz, 1H), 8.32 (s, 1H), 8.21 (d, J=5.1 Hz, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.31 (t, J=53.5 Hz, 1H), 7.04 (t, J=54.9 Hz, 1H), 3.96 (s, 2H), 3.46 (s, 2H), 1.80 (dp, J=12.5, 6.7, 6.3 Hz, 1H), 1.45 (qd, J=14.1, 5.6 Hz, 2H), 1.17 (s, 3H), 0.92 (dd, J=13.6, 6.6 Hz, 6H); 19F NMR (376 MHz, DMSO-d 6) δ −115.43 (d, J=55.2 Hz), −117.78-−119.55 (m); LCMS (ESI) m/e 386.0 [(M+H) +, calcd C 19H 24F 4N 3O, 386.2]; LC/MS retention time (method B): t R=1.85 min.

SYN

WO-2021216454-A1

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021216441&_cid=P11-MI4EP8-16561-2

REF

• Discovery and Optimization of Biaryl Alkyl Ethers as a Novel Class of Highly Selective, CNS-Penetrable, and Orally Active Adaptor Protein-2-Associated Kinase 1 (AAK1) Inhibitors for the Potential Treatment of Neuropathic PainPublication Name: Journal of Medicinal ChemistryPublication Date: 2022-03-09PMID: 35261239DOI: 10.1021/acs.jmedchem.1c02132
• Discovery of (S)-1-((2′,6-Bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211): A Highly Selective, CNS Penetrable, and Orally Active Adaptor Protein-2 Associated Kinase 1 Inhibitor in Clinical Trials for the Treatment of Neuropathic PainPublication Name: Journal of Medicinal ChemistryPublication Date: 2022-03-08PMID: 35257579DOI: 10.1021/acs.jmedchem.1c02131
• Discovery, Structure–Activity Relationships, and In Vivo Evaluation of Novel Aryl Amides as Brain Penetrant Adaptor Protein 2-Associated Kinase 1 (AAK1) Inhibitors for the Treatment of Neuropathic PainPublication Name: Journal of Medicinal ChemistryPublication Date: 2021-07-16PMID: 34270254DOI: 10.1021/acs.jmedchem.1c00472

PAT

• Biaryl kinase inhibitorsPublication Number: US-2021277001-A1Priority Date: 2014-04-02
• Biaryl kinase inhibitorsPublication Number: KR-102379518-B1Priority Date: 2014-04-02Grant Date: 2022-03-25
• Biaryl kinase inhibitorsPublication Number: US-12065437-B2Priority Date: 2014-04-02Grant Date: 2024-08-20
• Biaryl kinase inhibitorsPublication Number: US-2024360131-A1Priority Date: 2014-04-02

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////////////Pilavapadin, LX9211, BMS-986176, LX 9211,  BMS 986176, Phase 2, Neuropathic pain, Postherpetic neuralgia, AAK1-IN-1, 9G4RLM5X6Z