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11 results on '"Xiong, Tina"'

1. Discovery and Optimization of N‑Heteroaryl Indazole LRRK2 Inhibitors.

Author

Logan, Kaitlyn M., Kaplan, Will, Simov, Vladimir, Zhou, Hua, Li, Derun, Torres, Luis, Morriello, Gregori J., Acton, John J., Pio, Barbara, Chen, Yi-Heng, Keylor, Mitchell H., Johnson, Rebecca, Kattar, Solomon D., Chau, Ryan, Yan, Xin, Ardolino, Michael, Zarate, Cayetana, Otte, Karin M., Palte, Rachel L., and Xiong, Tina

Published
2024
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2. Discovery of MK-1468: A Potent, Kinome-Selective, Brain-Penetrant Amidoisoquinoline LRRK2 Inhibitor for the Potential Treatment of Parkinson's Disease.

Author

Kattar, Solomon D., Gulati, Anmol, Margrey, Kaila A., Keylor, Mitchell H., Ardolino, Michael, Yan, Xin, Johnson, Rebecca, Palte, Rachel L., McMinn, Spencer E., Nogle, Lisa, Su, Jing, Xiao, Dong, Piesvaux, Jennifer, Lee, Susi, Hegde, Laxminarayan G., Woodhouse, Janice D., Faltus, Robert, Moy, Lily Y., Xiong, Tina, and Ciaccio, Paul J.

Published
2023
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3. Discovery and Optimization of Potent, Selective, and Brain-Penetrant 1-Heteroaryl-1H-Indazole LRRK2 Kinase Inhibitors for the Treatment of Parkinson’s Disease

Author

Candito, David A., primary, Simov, Vladimir, additional, Gulati, Anmol, additional, Kattar, Solomon, additional, Chau, Ryan W., additional, Lapointe, Blair T., additional, Methot, Joey L., additional, DeMong, Duane E., additional, Graham, Thomas H., additional, Kurukulasuriya, Ravi, additional, Keylor, Mitchell H., additional, Tong, Ling, additional, Morriello, Gregori J., additional, Acton, John J., additional, Pio, Barbara, additional, Liu, Weiguo, additional, Scott, Jack D., additional, Ardolino, Michael J., additional, Martinot, Theodore A., additional, Maddess, Matthew L., additional, Yan, Xin, additional, Gunaydin, Hakan, additional, Palte, Rachel L., additional, McMinn, Spencer E., additional, Nogle, Lisa, additional, Yu, Hongshi, additional, Minnihan, Ellen C., additional, Lesburg, Charles A., additional, Liu, Ping, additional, Su, Jing, additional, Hegde, Laxminarayan G., additional, Moy, Lily Y., additional, Woodhouse, Janice D., additional, Faltus, Robert, additional, Xiong, Tina, additional, Ciaccio, Paul, additional, Piesvaux, Jennifer A., additional, Otte, Karin M., additional, Kennedy, Matthew E., additional, Bennett, David Jonathan, additional, DiMauro, Erin F., additional, Fell, Matthew J., additional, Neelamkavil, Santhosh, additional, Wood, Harold B., additional, Fuller, Peter H., additional, and Ellis, J. Michael, additional

Published
2022
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4. Structure-Guided Discovery of Aminoquinazolines as Brain-Penetrant and Selective LRRK2 Inhibitors

Author

Keylor, Mitchell H., primary, Gulati, Anmol, additional, Kattar, Solomon D., additional, Johnson, Rebecca E., additional, Chau, Ryan W., additional, Margrey, Kaila A., additional, Ardolino, Michael J., additional, Zarate, Cayetana, additional, Poremba, Kelsey E., additional, Simov, Vladimir, additional, Morriello, Gregori J., additional, Acton, John J., additional, Pio, Barbara, additional, Yan, Xin, additional, Palte, Rachel L., additional, McMinn, Spencer E., additional, Nogle, Lisa, additional, Lesburg, Charles A., additional, Adpressa, Donovon, additional, Lin, Shishi, additional, Neelamkavil, Santhosh, additional, Liu, Ping, additional, Su, Jing, additional, Hegde, Laxminarayan G., additional, Woodhouse, Janice D., additional, Faltus, Robert, additional, Xiong, Tina, additional, Ciaccio, Paul J., additional, Piesvaux, Jennifer, additional, Otte, Karin M., additional, Wood, Harold B., additional, Kennedy, Matthew E., additional, Bennett, David Jonathan, additional, DiMauro, Erin F., additional, Fell, Matthew J., additional, and Fuller, Peter H., additional

Published
2021
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10. Discovery and Optimization of Potent, Selective, and Brain-Penetrant 1-Heteroaryl-1 H -Indazole LRRK2 Kinase Inhibitors for the Treatment of Parkinson's Disease.

Author

Candito DA, Simov V, Gulati A, Kattar S, Chau RW, Lapointe BT, Methot JL, DeMong DE, Graham TH, Kurukulasuriya R, Keylor MH, Tong L, Morriello GJ, Acton JJ, Pio B, Liu W, Scott JD, Ardolino MJ, Martinot TA, Maddess ML, Yan X, Gunaydin H, Palte RL, McMinn SE, Nogle L, Yu H, Minnihan EC, Lesburg CA, Liu P, Su J, Hegde LG, Moy LY, Woodhouse JD, Faltus R, Xiong T, Ciaccio P, Piesvaux JA, Otte KM, Kennedy ME, Bennett DJ, DiMauro EF, Fell MJ, Neelamkavil S, Wood HB, Fuller PH, and Ellis JM

Subjects
Rats, Humans, Animals, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Indazoles pharmacology, Indazoles therapeutic use, Leukocytes, Mononuclear metabolism, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors chemistry, Brain metabolism, Adenosine Triphosphate, Parkinson Disease drug therapy
Abstract

Inhibition of leucine-rich repeat kinase 2 (LRRK2) kinase activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson's disease. Herein, we describe the optimization of a novel series of potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1 H -indazole type I (ATP competitive) LRRK2 inhibitors. Type I ATP-competitive kinase physicochemical properties were integrated with CNS drug-like properties through a combination of structure-based drug design and parallel medicinal chemistry enabled by sp 3 -sp 2 cross-coupling technologies. This resulted in the discovery of a unique sp 3 -rich spirocarbonitrile motif that imparted extraordinary potency, pharmacokinetics, and favorable CNS drug-like properties. The lead compound, 25 , demonstrated exceptional on-target potency in human peripheral blood mononuclear cells, excellent off-target kinase selectivity, and good brain exposure in rat, culminating in a low projected human dose and a pre-clinical safety profile that warranted advancement toward pre-clinical candidate enabling studies.

Published
2022
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11. Structure-Guided Discovery of Aminoquinazolines as Brain-Penetrant and Selective LRRK2 Inhibitors.

Author

Keylor MH, Gulati A, Kattar SD, Johnson RE, Chau RW, Margrey KA, Ardolino MJ, Zarate C, Poremba KE, Simov V, Morriello GJ, Acton JJ, Pio B, Yan X, Palte RL, McMinn SE, Nogle L, Lesburg CA, Adpressa D, Lin S, Neelamkavil S, Liu P, Su J, Hegde LG, Woodhouse JD, Faltus R, Xiong T, Ciaccio PJ, Piesvaux J, Otte KM, Wood HB, Kennedy ME, Bennett DJ, DiMauro EF, Fell MJ, and Fuller PH

Subjects
Antiparkinson Agents pharmacokinetics, Biological Availability, Drug Design, Humans, Models, Molecular, Protein Kinase Inhibitors pharmacology, Quinazolines pharmacokinetics, Structure-Activity Relationship, Antiparkinson Agents chemical synthesis, Antiparkinson Agents pharmacology, Brain metabolism, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 antagonists & inhibitors, Quinazolines chemical synthesis, Quinazolines pharmacology
Abstract

The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds 22 and 24 . These compounds exhibit remarkable selectivity against the kinome and offer good oral bioavailability and low projected human doses. Furthermore, they showcase the implementation of stereochemical design elements that serve to enable a potency- and selectivity-enhancing increase in polarity and hydrogen bond donor (HBD) count while maintaining a central nervous system-friendly profile typified by low levels of transporter-mediated efflux and encouraging brain penetration in preclinical models.

Published
2022
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