261352-96-9Relevant academic research and scientific papers
Tetrahydroindazoles as interleukin-2 inducible T-cell kinase inhibitors. Part II. Second-generation analogues with enhanced potency, selectivity, and pharmacodynamic modulation in vivo
Burch, Jason D.,Barrett, Kathy,Chen, Yuan,DeVoss, Jason,Eigenbrot, Charles,Goldsmith, Richard,Ismaili, M. Hicham A.,Lau, Kevin,Lin, Zhonghua,Ortwine, Daniel F.,Zarrin, Ali A.,McEwan, Paul A.,Barker, John J.,Ellebrandt, Claire,Kordt, Daniel,Stein, Daniel B.,Wang, Xiaolu,Chen, Yong,Hu, Baihua,Xu, Xiaofeng,Yuen, Po-Wai,Zhang, Yamin,Pei, Zhonghua
, p. 3806 - 3816 (2015)
The medicinal chemistry community has directed considerable efforts toward the discovery of selective inhibitors of interleukin-2 inducible T-cell kinase (ITK), given its role in T-cell signaling downstream of the T-cell receptor (TCR) and the implications of this target for inflammatory disorders such as asthma. We have previously disclosed a structure- and property-guided lead optimization effort which resulted in the discovery of a new series of tetrahydroindazole-containing selective ITK inhibitors. Herein we disclose further optimization of this series that resulted in further potency improvements, reduced off-target receptor binding liabilities, and reduced cytotoxicity. Specifically, we have identified a correlation between the basicity of solubilizing elements in the ITK inhibitors and off-target antiproliferative effects, which was exploited to reduce cytotoxicity while maintaining kinase selectivity. Optimized analogues were shown to reduce IL-2 and IL-13 production in vivo following oral or intraperitoneal dosing in mice.
Stereochemistry of addition of organometallic reagents to 2-acyloxanes and 2-acylthianes
Alvarez-Wright, Maria Teresa,Satici, Hikmet,Eliel, Ernest L.,White, Peter S.
, p. 617 - 629 (2007/10/03)
The stereochemistry of addition of a number of organometallic reagents, including methyllithium, methyllithium-YbCl3, 1-pentynyllithium, and 1-pentynyllithium-YbCl3 to 2-acyloxanes, 2-benzoylthianes, several substituted 1,3-oxathianes and 2-methoxyacetylthiane has been studied. For the ring systems containing oxygen atoms, almost all of the additions proceed in accordance with Cram's chelate rule, on the assumption that the chelation takes place with the oxygen rather than the sulfur atoms of the ring where both are present. An exception (cf. Utimoto et al.7) is the addition of 1-pentynyllithium-YbCl3 to conformationally locked 1,3-oxathianes; however, addition of methyllithium-YbCl3 to all 1,3-oxathianes studied and of pentynyllithium-YbCl3 to the conformationally mobile 2-benzoyl-1,3-oxathiane proceeds 'normally'. Additions to 2-benzoylthiane are usually of low stereoselectivity and often proceed contrary to what would be predicted on the assumption that the organometallic reagent chelates with sulfur; an exception is methylmagnesium iodide which does follow Cram's chelate rule. The additions of RLi and RLi.YbCl3 (R methyl or 1-pentynyl) to 2-benzoylthiane follow the same stereochemical course presumably proceeding contrary to Cram's chelate rule; thus the reversal observed with 1-pentynyllithium-YbCl3 in the 1,3-oxathiane series appears not to be due to chelation with sulfur. The results with 2-methoxyacetylthiane suggest that chelation with the side-chain oxygen substituent prevails over chelation with the ring sulfur atom.
