Bruton’s tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.

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N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 [N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, BMS-387032], has been identified as an ATP-competitive and CDK2-selective inhibitor which has been selected to enter Phase 1 human clinical trials as an antitumor agent. In a cell-free enzyme assay, 21 showed a CDK2/cycE IC(50) = 48 nM and was 10- and 20-fold selective over CDK1/cycB and CDK4/cycD, respectively. It was also highly selective over a panel of 12 unrelated kinases. Antiproliferative activity was established in an A2780 cellular cytotoxicity assay in which 21 showed an IC(50) = 95 nM. Metabolism and pharmacokinetic studies showed that 21 exhibited a plasma half-life of 5-7 h in three species and moderately low protein binding in both mouse (69%) and human (63%) serum. Dosed orally to mouse, rat, and dog, 21 showed 100%, 31%, and 28% bioavailability, respectively. As an antitumor agent in mice, 21 administered at its maximum-tolerated dose exhibited a clearly superior efficacy profile when compared to flavopiridol in both an ip/ip P388 murine tumor model and in a s.c./i.p. A2780 human ovarian carcinoma xenograft model.

Antibiotic resistance is a major cause of Helicobacter pylori (H. pylori) treatment failures. Because the resistance rate of H. pylori to furazolidone is low, we aimed to assess the efficacy and safety of furazolidone. We searched the PubMed, Web of Science, Cochrane Library, and Embase databases and included randomized controlled trials (RCT) that either compared furazolidone to other antibiotics or changed the administered dose of furazolidone. A total of 18 articles were included in the meta-analysis. According to the intention-to-treat (ITT) analysis, the total eradication rates of furazolidone-containing therapy were superior to those of other antibiotic-containing therapies (relative risk [RR] 1.07, 95% confidence interval [CI] 1.01-1.14) (13 RCTs). Specifically, the eradication rates of furazolidone-containing therapy were better than those for metronidazole-containing therapy (RR 1.10, 95% CI: 1.01-1.21 for ITT). The eradication rate of furazolidone-containing bismuth-containing quadruple therapy was 92.9% (95% CI: 90.7%-95.1%) (PP). In addition, a higher daily dose of furazolidone increased the eradication rate (RR 1.17, 95% CI: 1.05-1.31). And the incidence of some adverse effects, such as fever and anorexia, was higher in the furazolidone group than in the control group, the overall incidences of total side effects and severe side effects showed no significant differences between the groups. Furazolidone-containing treatments could achieve satisfactory eradication rates and did not increase the incidence of total or severe adverse effects, but the incidence of milder side effects, such as fever and anorexia, should be considered when prescribing furazolidone-containing treatments to patients.