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 Pain

Guanglin Luo; Ling Chen; Walter A. Kostich; Brian Hamman; Jason Allen; Amy Easton; Clotilde Bourin; Michael Gulianello; Jonathan Lippy; Susheel Nara; Tarun Kumar Maishal; Kamalraj Thiyagarajan; Prasadrao Jalagam; Sreenivasulu Naidu Pattipati; Kumaran Dandapani; Manoj Dokania; Pradeep Vattikundala; Vivek Sharma; Saravanan Elavazhagan; Manoj Kumar Verma; Manish Lal Das; Santosh Wagh; Anand Balakrishnan; Benjamin M. Johnson; Kenneth S. Santone; George Thalody; Rex Denton; Hariharan Saminathan; Vinay K. Holenarsipur; Anoop Kumar; Abhijith Rao; Siva Prasad Putlur; Sarat Kumar Sarvasiddhi; Ganesh Shankar; Justin V. Louis; Manjunath Ramarao; Charles M. Conway; Yu Wen Li; Rick Pieschl; Yuan Tian; Yang Hong; Jonathan Ditta; Arvind Mathur; Jianqing Li; Daniel Smith; Joseph Pawluczyk; Dawn Sun; Shiuhang Yip; Dauh Rurng Wu; Muthalagu Vetrichelvan; Anuradha Gupta; Alan Wilson; Suma Gopinathan; Suman Wason; Linda Bristow; Charles F. Albright; Joanne J. Bronson; John E. MacOr; Carolyn D. Dzierba

doi:10.1021/acs.jmedchem.1c02131

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 Pain

Guanglin Luo, Ling Chen, Walter A. Kostich, Brian Hamman, Jason Allen, Amy Easton, Clotilde Bourin, Michael Gulianello, Jonathan Lippy, Susheel Nara, Tarun Kumar Maishal, Kamalraj Thiyagarajan, Prasadrao Jalagam, Sreenivasulu Naidu Pattipati, Kumaran Dandapani, Manoj Dokania, Pradeep Vattikundala, Vivek Sharma, Saravanan Elavazhagan, Manoj Kumar VermaManish Lal Das, Santosh Wagh, Anand Balakrishnan, Benjamin M. Johnson, Kenneth S. Santone, George Thalody, Rex Denton, Hariharan Saminathan, Vinay K. Holenarsipur, Anoop Kumar, Abhijith Rao, Siva Prasad Putlur, Sarat Kumar Sarvasiddhi, Ganesh Shankar, Justin V. Louis, Manjunath Ramarao, Charles M. Conway, Yu Wen Li, Rick Pieschl, Yuan Tian, Yang Hong, Jonathan Ditta, Arvind Mathur, Jianqing Li, Daniel Smith, Joseph Pawluczyk, Dawn Sun, Shiuhang Yip, Dauh Rurng Wu, Muthalagu Vetrichelvan, Anuradha Gupta, Alan Wilson, Suma Gopinathan, Suman Wason, Linda Bristow, Charles F. Albright, Joanne J. Bronson, John E. MacOr, Carolyn D. Dzierba

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

Abstract

Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been identified and show efficacy in various rodent pain models. (S)-1-((2′,6-Bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211) (34) was identified as a highly selective, CNS penetrant, potent AAK1 inhibitor from a novel class of bi(hetero)aryl ethers. BMS-986176/LX9211 (34) showed excellent efficacy in two rodent neuropathic pain models and excellent central nervous system (CNS) penetration and target engagement at the spinal cord with an average brain to plasma ratio of 20 in rat. The compound exhibited favorable physicochemical and pharmacokinetic properties, had an acceptable preclinical toxicity profile, and was chosen for clinical trials. BMS-986176/LX9211 (34) completed phase I trials with good human pharmacokinetics and minimum adverse events and is currently in phase II clinical trials for diabetic peripheral neuropathic pain (ClinicalTrials.gov identifier: NCT04455633) and postherpetic neuralgia (ClinicalTrials.gov identifier: NCT04662281).

Original language	English
Pages (from-to)	4457-4480
Number of pages	24
Journal	Journal of Medicinal Chemistry
Volume	65
Issue number	6
DOIs	https://doi.org/10.1021/acs.jmedchem.1c02131
Publication status	Published - Mar 24 2022
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Luo, G., Chen, L., Kostich, W. A., Hamman, B., Allen, J., Easton, A., Bourin, C., Gulianello, M., Lippy, J., Nara, S., Maishal, T. K., Thiyagarajan, K., Jalagam, P., Pattipati, S. N., Dandapani, K., Dokania, M., Vattikundala, P., Sharma, V., Elavazhagan, S., ... Dzierba, C. D. (2022). 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 Pain. Journal of Medicinal Chemistry, 65(6), 4457-4480. https://doi.org/10.1021/acs.jmedchem.1c02131

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 Pain. / Luo, Guanglin; Chen, Ling; Kostich, Walter A. et al.
In: Journal of Medicinal Chemistry, Vol. 65, No. 6, 24.03.2022, p. 4457-4480.

Research output: Contribution to journal › Article › peer-review

Luo, G, Chen, L, Kostich, WA, Hamman, B, Allen, J, Easton, A, Bourin, C, Gulianello, M, Lippy, J, Nara, S, Maishal, TK, Thiyagarajan, K, Jalagam, P, Pattipati, SN, Dandapani, K, Dokania, M, Vattikundala, P, Sharma, V, Elavazhagan, S, Verma, MK, Das, ML, Wagh, S, Balakrishnan, A, Johnson, BM, Santone, KS, Thalody, G, Denton, R, Saminathan, H, Holenarsipur, VK, Kumar, A, Rao, A, Putlur, SP, Sarvasiddhi, SK, Shankar, G, Louis, JV, Ramarao, M, Conway, CM, Li, YW, Pieschl, R, Tian, Y, Hong, Y, Ditta, J, Mathur, A, Li, J, Smith, D, Pawluczyk, J, Sun, D, Yip, S, Wu, DR, Vetrichelvan, M, Gupta, A, Wilson, A, Gopinathan, S, Wason, S, Bristow, L, Albright, CF, Bronson, JJ, MacOr, JE & Dzierba, CD 2022, '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 Pain', Journal of Medicinal Chemistry, vol. 65, no. 6, pp. 4457-4480. https://doi.org/10.1021/acs.jmedchem.1c02131

Luo G, Chen L, Kostich WA, Hamman B, Allen J, Easton A et al. 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 Pain. Journal of Medicinal Chemistry. 2022 Mar 24;65(6):4457-4480. doi: 10.1021/acs.jmedchem.1c02131

Luo, Guanglin ; Chen, Ling ; Kostich, Walter A. et al. / 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 Pain. In: Journal of Medicinal Chemistry. 2022 ; Vol. 65, No. 6. pp. 4457-4480.

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title = "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 Pain",

abstract = "Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been identified and show efficacy in various rodent pain models. (S)-1-((2′,6-Bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211) (34) was identified as a highly selective, CNS penetrant, potent AAK1 inhibitor from a novel class of bi(hetero)aryl ethers. BMS-986176/LX9211 (34) showed excellent efficacy in two rodent neuropathic pain models and excellent central nervous system (CNS) penetration and target engagement at the spinal cord with an average brain to plasma ratio of 20 in rat. The compound exhibited favorable physicochemical and pharmacokinetic properties, had an acceptable preclinical toxicity profile, and was chosen for clinical trials. BMS-986176/LX9211 (34) completed phase I trials with good human pharmacokinetics and minimum adverse events and is currently in phase II clinical trials for diabetic peripheral neuropathic pain (ClinicalTrials.gov identifier: NCT04455633) and postherpetic neuralgia (ClinicalTrials.gov identifier: NCT04662281).",

author = "Guanglin Luo and Ling Chen and Kostich, {Walter A.} and Brian Hamman and Jason Allen and Amy Easton and Clotilde Bourin and Michael Gulianello and Jonathan Lippy and Susheel Nara and Maishal, {Tarun Kumar} and Kamalraj Thiyagarajan and Prasadrao Jalagam and Pattipati, {Sreenivasulu Naidu} and Kumaran Dandapani and Manoj Dokania and Pradeep Vattikundala and Vivek Sharma and Saravanan Elavazhagan and Verma, {Manoj Kumar} and Das, {Manish Lal} and Santosh Wagh and Anand Balakrishnan and Johnson, {Benjamin M.} and Santone, {Kenneth S.} and George Thalody and Rex Denton and Hariharan Saminathan and Holenarsipur, {Vinay K.} and Anoop Kumar and Abhijith Rao and Putlur, {Siva Prasad} and Sarvasiddhi, {Sarat Kumar} and Ganesh Shankar and Louis, {Justin V.} and Manjunath Ramarao and Conway, {Charles M.} and Li, {Yu Wen} and Rick Pieschl and Yuan Tian and Yang Hong and Jonathan Ditta and Arvind Mathur and Jianqing Li and Daniel Smith and Joseph Pawluczyk and Dawn Sun and Shiuhang Yip and Wu, {Dauh Rurng} and Muthalagu Vetrichelvan and Anuradha Gupta and Alan Wilson and Suma Gopinathan and Suman Wason and Linda Bristow and Albright, {Charles F.} and Bronson, {Joanne J.} and MacOr, {John E.} and Dzierba, {Carolyn D.}",

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year = "2022",

month = mar,

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doi = "10.1021/acs.jmedchem.1c02131",

language = "English",

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T1 - Discovery of (S)-1-((2′,6-Bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211)

T2 - A Highly Selective, CNS Penetrable, and Orally Active Adaptor Protein-2 Associated Kinase 1 Inhibitor in Clinical Trials for the Treatment of Neuropathic Pain

AU - Luo, Guanglin

AU - Chen, Ling

AU - Kostich, Walter A.

AU - Hamman, Brian

AU - Allen, Jason

AU - Easton, Amy

AU - Bourin, Clotilde

AU - Gulianello, Michael

AU - Lippy, Jonathan

AU - Nara, Susheel

AU - Maishal, Tarun Kumar

AU - Thiyagarajan, Kamalraj

AU - Jalagam, Prasadrao

AU - Pattipati, Sreenivasulu Naidu

AU - Dandapani, Kumaran

AU - Dokania, Manoj

AU - Vattikundala, Pradeep

AU - Sharma, Vivek

AU - Elavazhagan, Saravanan

AU - Verma, Manoj Kumar

AU - Das, Manish Lal

AU - Wagh, Santosh

AU - Balakrishnan, Anand

AU - Johnson, Benjamin M.

AU - Santone, Kenneth S.

AU - Thalody, George

AU - Denton, Rex

AU - Saminathan, Hariharan

AU - Holenarsipur, Vinay K.

AU - Kumar, Anoop

AU - Rao, Abhijith

AU - Putlur, Siva Prasad

AU - Sarvasiddhi, Sarat Kumar

AU - Shankar, Ganesh

AU - Louis, Justin V.

AU - Ramarao, Manjunath

AU - Conway, Charles M.

AU - Li, Yu Wen

AU - Pieschl, Rick

AU - Tian, Yuan

AU - Hong, Yang

AU - Ditta, Jonathan

AU - Mathur, Arvind

AU - Li, Jianqing

AU - Smith, Daniel

AU - Pawluczyk, Joseph

AU - Sun, Dawn

AU - Yip, Shiuhang

AU - Wu, Dauh Rurng

AU - Vetrichelvan, Muthalagu

AU - Gupta, Anuradha

AU - Wilson, Alan

AU - Gopinathan, Suma

AU - Wason, Suman

AU - Bristow, Linda

AU - Albright, Charles F.

AU - Bronson, Joanne J.

AU - MacOr, John E.

AU - Dzierba, Carolyn D.

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N2 - Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been identified and show efficacy in various rodent pain models. (S)-1-((2′,6-Bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211) (34) was identified as a highly selective, CNS penetrant, potent AAK1 inhibitor from a novel class of bi(hetero)aryl ethers. BMS-986176/LX9211 (34) showed excellent efficacy in two rodent neuropathic pain models and excellent central nervous system (CNS) penetration and target engagement at the spinal cord with an average brain to plasma ratio of 20 in rat. The compound exhibited favorable physicochemical and pharmacokinetic properties, had an acceptable preclinical toxicity profile, and was chosen for clinical trials. BMS-986176/LX9211 (34) completed phase I trials with good human pharmacokinetics and minimum adverse events and is currently in phase II clinical trials for diabetic peripheral neuropathic pain (ClinicalTrials.gov identifier: NCT04455633) and postherpetic neuralgia (ClinicalTrials.gov identifier: NCT04662281).

AB - Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been identified and show efficacy in various rodent pain models. (S)-1-((2′,6-Bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211) (34) was identified as a highly selective, CNS penetrant, potent AAK1 inhibitor from a novel class of bi(hetero)aryl ethers. BMS-986176/LX9211 (34) showed excellent efficacy in two rodent neuropathic pain models and excellent central nervous system (CNS) penetration and target engagement at the spinal cord with an average brain to plasma ratio of 20 in rat. The compound exhibited favorable physicochemical and pharmacokinetic properties, had an acceptable preclinical toxicity profile, and was chosen for clinical trials. BMS-986176/LX9211 (34) completed phase I trials with good human pharmacokinetics and minimum adverse events and is currently in phase II clinical trials for diabetic peripheral neuropathic pain (ClinicalTrials.gov identifier: NCT04455633) and postherpetic neuralgia (ClinicalTrials.gov identifier: NCT04662281).

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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 Pain

Abstract

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