Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes.Bioorg Med Chem Lett. 2020 Sep 01; 30(17):127390.BM
Abstract
Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.
Links
MeSH
Agammaglobulinaemia Tyrosine KinaseAnimalsArthritis, ExperimentalBinding SitesBridged Bicyclo CompoundsCrystallography, X-RayDisease Models, AnimalDogsDose-Response Relationship, DrugHalf-LifeHumansImidazolesMolecular Dynamics SimulationProtein Kinase InhibitorsPyrazinesRatsRats, WistarStructure-Activity Relationshipsrc-Family Kinases
Pub Type(s)
Journal Article
Language
eng
PubMed ID
32738973
Citation
Liu, Jian, et al. "Potent, Non-covalent Reversible BTK Inhibitors With 8-amino-imidazo[1,5-a]pyrazine Core Featuring 3-position Bicyclic Ring Substitutes." Bioorganic & Medicinal Chemistry Letters, vol. 30, no. 17, 2020, p. 127390.
Liu J, Guiadeen D, Krikorian A, et al. Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes. Bioorg Med Chem Lett. 2020;30(17):127390.
Liu, J., Guiadeen, D., Krikorian, A., Gao, X., Wang, J., Babu Boga, S., Alhassan, A. B., Yu, W., Selyutin, O., Yu, Y., Anand, R., Xu, J., Kelly, J., Duffy, J. L., Liu, S., Yang, C., Wu, H., Cai, J., Bennett, C., ... Kozlowski, J. A. (2020). Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes. Bioorganic & Medicinal Chemistry Letters, 30(17), 127390. https://doi.org/10.1016/j.bmcl.2020.127390
Liu J, et al. Potent, Non-covalent Reversible BTK Inhibitors With 8-amino-imidazo[1,5-a]pyrazine Core Featuring 3-position Bicyclic Ring Substitutes. Bioorg Med Chem Lett. 2020 09 1;30(17):127390. PubMed PMID: 32738973.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR
T1 - Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes.
AU - Liu,Jian,
AU - Guiadeen,Deodial,
AU - Krikorian,Arto,
AU - Gao,Xiaolei,
AU - Wang,James,
AU - Babu Boga,Sobhana,
AU - Alhassan,Abdul-Basit,
AU - Yu,Wensheng,
AU - Selyutin,Oleg,
AU - Yu,Younong,
AU - Anand,Rajan,
AU - Xu,Jiayi,
AU - Kelly,Joseph,
AU - Duffy,Joseph L,
AU - Liu,Shilan,
AU - Yang,Chundao,
AU - Wu,Hao,
AU - Cai,Jiaqiang,
AU - Bennett,Chad,
AU - Maloney,Kevin M,
AU - Tyagarajan,Sriram,
AU - Gao,Ying-Duo,
AU - Fischmann,Thierry O,
AU - Presland,Jeremy,
AU - Mansueto,My,
AU - Xu,Zangwei,
AU - Leccese,Erica,
AU - Zhang-Hoover,Jie,
AU - Knemeyer,Ian,
AU - Garlisi,Charles G,
AU - Stivers,Peter,
AU - Brandish,Philip E,
AU - Hicks,Alexandra,
AU - Kim,Ronald,
AU - Kozlowski,Joseph A,
Y1 - 2020/07/11/
PY - 2020/05/08/received
PY - 2020/07/01/revised
PY - 2020/07/03/accepted
PY - 2020/8/3/entrez
PY - 2020/8/3/pubmed
PY - 2021/6/9/medline
KW - Bruton’s Tyrosine Kinase
KW - Kinase selectivity
KW - Rat CIA model
KW - Structure based drug design
KW - X-ray crystal structure
SP - 127390
EP - 127390
JF - Bioorganic & medicinal chemistry letters
JO - Bioorg Med Chem Lett
VL - 30
IS - 17
N2 - Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.
SN - 1464-3405
UR - https://www.unboundmedicine.com/medline/citation/32738973
DB - PRIME
DP - Unbound Medicine
ER -
