191348-04-6Relevant articles and documents
Discovery of a Candidate Containing an (S)-3,3-Difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1 H-inden Scaffold as a Highly Potent Pan-Inhibitor of the BCR-ABL Kinase including the T315I-Resistant Mutant for the Treatment of Chronic Myeloid Leukemia
Zhang, Dongfeng,Li, Peng,Gao, Yongxin,Song, Yaoyao,Zhu, Yaqin,Su, Hong,Yang, Beibei,Li, Li,Li, Gang,Gong, Ningbo,Lu, Yang,Shao, Huanjie,Yu, Chunrong,Huang, Haihong
, p. 7434 - 7452 (2021/06/25)
BCR-ABL kinase inhibition is an effective strategy for the treatment of chronic myeloid leukemia (CML). Herein, we report compound 3a-P1, bearing a difluoro-indene scaffold, as a novel potent pan-inhibitor against BCR-ABL mutants, including the most refractory T315I mutant. As the privileged (S)-isomer compared to its (R)-isomer 3a-P2, 3a-P1 exhibited potent antiproliferative activities against K562 and Ku812 CML cells and BCR-ABL and BCR-ABLT315I BaF3 cells, with IC50 values of 0.4, 0.1, 2.1, and 4.7 nM, respectively. 3a-P1 displayed a good safety profile in a battery of assays, including single-dose toxicity, hERG K+, and genotoxicity. It also showed favorable mice pharmacokinetic properties with a good oral bioavailability (32%), a reasonable half-life (4.61 h), and a high exposure (1386 h·ng/mL). Importantly, 3a-P1 demonstrated a higher potency than ponatinib in a mice xenograft model of BaF3 harboring BCR-ABLT315I. Overall, the results indicate that 3a-P1 is a promising drug candidate for the treatment of CML to overcome the imatinib-resistant T315I BCR-ABL mutation.
MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR
-
Paragraph 00898, (2021/02/19)
This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing at least one such modulator, methods of treatment of cystic fibrosis using such modulators and pharmaceutical compositions, and processes for making such modulators.
C11-CYCLIC SUBSTITUTED 13-MEMBERED MACROLIDES AND USES THEREOF
-
Paragraph 00307; 00309; 00310, (2020/06/10)
Provided are 13-membered macrolides for the treatment of infectious diseases. The 13- membered macrolides described herein are azaketolides. Also provided are methods for preparing the 13-membered macrolides, pharmaceutical compositions comprising the 13-
