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Title: Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9 H -carbazole-1-carboxamide (BMS-935177)

Abstract

Bruton’s tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure–activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1347757
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Medicinal Chemistry; Journal Volume: 59; Journal Issue: 17
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

De Lucca, George V., Shi, Qing, Liu, Qingjie, Batt, Douglas G., Beaudoin Bertrand, Myra, Rampulla, Rick, Mathur, Arvind, Discenza, Lorell, D’Arienzo, Celia, Dai, Jun, Obermeier, Mary, Vickery, Rodney, Zhang, Yingru, Yang, Zheng, Marathe, Punit, Tebben, Andrew J., Muckelbauer, Jodi K., Chang, ChiehYing J., Zhang, Huiping, Gillooly, Kathleen, Taylor, Tracy, Pattoli, Mark A., Skala, Stacey, Kukral, Daniel W., McIntyre, Kim W., Salter-Cid, Luisa, Fura, Aberra, Burke, James R., Barrish, Joel C., Carter, Percy H., and Tino, Joseph A. Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9 H -carbazole-1-carboxamide (BMS-935177). United States: N. p., 2016. Web. doi:10.1021/acs.jmedchem.6b00722.
De Lucca, George V., Shi, Qing, Liu, Qingjie, Batt, Douglas G., Beaudoin Bertrand, Myra, Rampulla, Rick, Mathur, Arvind, Discenza, Lorell, D’Arienzo, Celia, Dai, Jun, Obermeier, Mary, Vickery, Rodney, Zhang, Yingru, Yang, Zheng, Marathe, Punit, Tebben, Andrew J., Muckelbauer, Jodi K., Chang, ChiehYing J., Zhang, Huiping, Gillooly, Kathleen, Taylor, Tracy, Pattoli, Mark A., Skala, Stacey, Kukral, Daniel W., McIntyre, Kim W., Salter-Cid, Luisa, Fura, Aberra, Burke, James R., Barrish, Joel C., Carter, Percy H., & Tino, Joseph A. Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9 H -carbazole-1-carboxamide (BMS-935177). United States. doi:10.1021/acs.jmedchem.6b00722.
De Lucca, George V., Shi, Qing, Liu, Qingjie, Batt, Douglas G., Beaudoin Bertrand, Myra, Rampulla, Rick, Mathur, Arvind, Discenza, Lorell, D’Arienzo, Celia, Dai, Jun, Obermeier, Mary, Vickery, Rodney, Zhang, Yingru, Yang, Zheng, Marathe, Punit, Tebben, Andrew J., Muckelbauer, Jodi K., Chang, ChiehYing J., Zhang, Huiping, Gillooly, Kathleen, Taylor, Tracy, Pattoli, Mark A., Skala, Stacey, Kukral, Daniel W., McIntyre, Kim W., Salter-Cid, Luisa, Fura, Aberra, Burke, James R., Barrish, Joel C., Carter, Percy H., and Tino, Joseph A. 2016. "Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9 H -carbazole-1-carboxamide (BMS-935177)". United States. doi:10.1021/acs.jmedchem.6b00722.
@article{osti_1347757,
title = {Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9 H -carbazole-1-carboxamide (BMS-935177)},
author = {De Lucca, George V. and Shi, Qing and Liu, Qingjie and Batt, Douglas G. and Beaudoin Bertrand, Myra and Rampulla, Rick and Mathur, Arvind and Discenza, Lorell and D’Arienzo, Celia and Dai, Jun and Obermeier, Mary and Vickery, Rodney and Zhang, Yingru and Yang, Zheng and Marathe, Punit and Tebben, Andrew J. and Muckelbauer, Jodi K. and Chang, ChiehYing J. and Zhang, Huiping and Gillooly, Kathleen and Taylor, Tracy and Pattoli, Mark A. and Skala, Stacey and Kukral, Daniel W. and McIntyre, Kim W. and Salter-Cid, Luisa and Fura, Aberra and Burke, James R. and Barrish, Joel C. and Carter, Percy H. and Tino, Joseph A.},
abstractNote = {Bruton’s tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure–activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.},
doi = {10.1021/acs.jmedchem.6b00722},
journal = {Journal of Medicinal Chemistry},
number = 17,
volume = 59,
place = {United States},
year = 2016,
month = 9
}