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Your search keyword '"Sarat Kumar Sarvasiddhi"' showing total 5 results
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5 results on '"Sarat Kumar Sarvasiddhi"'

1. 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 Pain

Author

Guanglin Luo, Ling Chen, Walter A. Kostich, Brian Hamman, Jason Allen, Amy Easton, Clotilde Bourin, Michael Gulianello, Jonathan Lippy, Susheel Nara, 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, Linda Bristow, Charles F. Albright, Joanne J. Bronson, John E. Macor, and Carolyn D. Dzierba

Subjects
Mice, Structure-Activity Relationship, Spinal Cord, Anesthetics, General, Drug Discovery, Animals, Neuralgia, Molecular Medicine, Protein Kinase Inhibitors, Ethers, Rats
Abstract

Recent mouse knockout studies identified adapter protein-2-associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. BMS-986176/LX-9211 (

Published
2022

2. 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

Author

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, and Carolyn D. Dzierba

Subjects
Drug Discovery, Molecular Medicine
Published
2022

3. Bicyclic Heterocyclic Replacement of an Aryl Amide Leading to Potent and Kinase-Selective Adaptor Protein 2-Associated Kinase 1 Inhibitors

Author

Richard A. Hartz, Vijay T. Ahuja, Susheel J. Nara, C. M. Vijaya Kumar, Raju K. V. L. P. Manepalli, Sarat Kumar Sarvasiddhi, Swarnamba Honkhambe, Vidya Patankar, Bireshwar Dasgupta, Ramkumar Rajamani, Jodi K. Muckelbauer, Daniel M. Camac, Kaushik Ghosh, Matthew Pokross, Susan E. Kiefer, Jeffrey M. Brown, Lisa Hunihan, Michael Gulianello, Martin Lewis, Jonathan S. Lippy, Neha Surti, Brian D. Hamman, Jason Allen, Walter A. Kostich, Joanne J. Bronson, John E. Macor, and Carolyn D. Dzierba

Subjects
Structure-Activity Relationship, Drug Discovery, Quinazolines, Quinolines, Animals, Neuralgia, Molecular Medicine, Amides, Protein Kinase Inhibitors
Abstract

Adaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound

Published
2022

4. Discovery of (

Author

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, and Carolyn D, Dzierba

Subjects
Mice, Spinal Cord, Animals, Brain, Neuralgia, Amines, Protein Kinase Inhibitors, Rats
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. (

Published
2022

5. [ 3 H]BMT-046091 a potent and selective radioligand to determine AAK1 distribution and target engagement

Author

Justin Vijay Louis, Kumaran Dandapani, Susheel J. Nara, Yang Hong, Yung Tian, Sarat Kumar Sarvasiddhi, Yifeng Lu, Carolyn Diane Dzierba, Walter Kostich, Yu-Wen Li, Rick L. Pieschl, Sreenivasulu Naidu, Charlie F. Albright, Joanne J. Bronson, John E. Macor, and Reeba K. Vikramadithyan

Subjects
0301 basic medicine, Pharmacology, Kinase, Central nervous system, Biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Nociception, Knockout mouse, Radioligand, medicine, Phosphorylation, Binding site, Receptor, Neuroscience, 030217 neurology & neurosurgery
Abstract

Adaptor-associated kinase 1 (AAK1), a member of the Ark1/Prk1 family of serine/threonine kinases, plays a role in modulating clatherin coated endocytosis of specific surface receptors. We have demonstrated that AAK1 inhibitors are efficacious in rodent models of neuropathic pain (Kostich et al., 2016). Here we have characterized the binding properties and distribution pattern of the tritiated AAK1 radioligand, [3H]BMT-046091, in rodents and cynomolgus monkeys, and used the radioligand to measure the brain target occupancy following systemic administration of AAK1 inhibitors. We have found that [3H]BMT-046091 is potent and selective AAK1 inhibitor. It inhibits AAK1 phosphorylation of a peptide derived from a physiologic substrate, the μ2 subunit of the adaptor protein complex, with an IC50 value of 2.8 nM, and is inactive at >5 μM in a panel of functional or binding assays for receptors, transporters and enzymes. [3H]BMT-046091 binding in the brain is absent in the AAK1 knockout mouse, and is displaceable with a high concentration of AAK1 inhibitors in wild type mice. Specific [3H]BMT-046091 binding is widespread in the brain and spinal cord with the highest density in the cortex, hippocampus, amygdala, striatum and thalamus. In the spinal cord, [3H]BMT-046091 binding appears enriched in the dorsal horn superficial layers. Oral administration of LP-935509, an AAK1 inhibitor, results in a dose-dependent occupation of AAK1 binding sites in the brain and spinal cord. The increase in AAK1 binding site occupancy by LP-935509 correlates with the decrease in antinociceptive responses in the rat chronic constriction injury model of neuropathic pain.

Published
2017

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