- Synthesis and biological evaluation of novel pyrazolo[1,5-a]pyrimidines: Discovery of a selective inhibitor of JAK1 JH2 pseudokinase and VPS34
-
A series of novel 3,6-di-substituted or 3-substituted pyrazolo[1,5-a]pyrimidines were prepared via a microwave-assisted approach that generated a broad array of derivatives in good yields (20–93%, ave. = 59%). The straightforward synthesis involved sequential treatment of commercially-available acetonitrile derivatives with DMF-dimethylacetal (120 °C, 20 min), followed by treatment with NH2NH2·HBr (120 °C, 20 min), and 1,1,3,3-tetramethoxypropane or 2-aryl-substituted malondialdehdyes (120 °C, 20 min). Compounds were screened for antimitotic activities against MCF7 breast cancer and/or A2780 ovarian cancer cell lines in vitro. The most active compounds exhibited EC50 values ranging from 0.5 to 4.3 μM, with the 3-(4-(trifluoromethyl)phenyl)-6-[4-(2-(piperidin-1-yl)ethoxy]phenyl analogue (34e) and the 3-(2-fluorophenyl)-6-[4-(2-(4-methylpiperizin-1-yl)ethoxy]phenyl analogue (35a) being two to three fold more active than Compound C (Dorsomorphin) in A2780 and MCF7 assays, respectively. Importantly, a monosubstituted 3-(benzothiazol-2-yl) derivative (13) was equipotent with the more synthetically challenging 3,6-disubstituted derivatives (34a–e and 35a–e), and exhibited a promising and unique selectivity profile when screened against a panel consisting of 403 protein kinases (Kinomescan selectivity score = 0.005, Kd = 0.55 ± 0.055 μM and 0.410 ± 0.20 μM for JAK1 JH2 pseudokinase and VPS34, respectively).
- Singleton, Justin D.,Dass, Reuben,Neubert, Nathaniel R.,Smith, Rachel M.,Webber, Zak,Hansen, Marc D.H.,Peterson, Matt A.
-
supporting information
(2019/12/24)
-
- Novel tricyclic pyrazolopyrimidines as potent and selective GPR119 agonists
-
Systematic SAR optimization of the GPR119 agonist lead 1, derived from an internal HTS campaign, led to compound 29. Compound 29 displays significantly improved in vitro activity and oral exposure, leading to GLP1 elevation in acutely dosed mice and reduc
- Azimioara, Mihai,Alper, Phil,Cow, Christopher,Mutnick, Daniel,Nikulin, Victor,Lelais, Gerald,Mecom, John,McNeill, Matthew,Michellys, Pierre-Yves,Wang, Zhiliang,Reding, Esther,Paliotti, Michael,Li, Jing,Bao, Dingjiu,Zoll, Jocelyn,Kim, Young,Zimmerman, Matthew,Groessl, Todd,Tuntland, Tove,Joseph, Sean B.,McNamara, Peter,Seidel, H. Martin,Epple, Robert
-
supporting information
p. 5478 - 5483
(2015/01/09)
-