Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 18, Issue 11, Pages 3219-3223Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2008.04.048
Keywords
cell death; necrosis; necroptosis; microsome stability; caspase-independent; pyrroles; SAR
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Funding
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R21NS067497, U01NS050560] Funding Source: NIH RePORTER
- NINDS NIH HHS [U01 NS050560-02, R21 NS067497, U01 NS050560] Funding Source: Medline
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Necroptosis is a regulated caspase-independent cell death pathway resulting in morphology reminiscent of passive nonregulated necrosis. Several diverse structure classes of necroptosis inhibitors have been reported to date, including a series of [1,2,3] thiadiazole benzylamide derivatives. However, initial evaluation of mouse liver microsome stability indicated that this series of compounds was rapidly degraded. A structure-activity relationship (SAR) study of the [1,2,3] thiadiazole benzylamide series revealed that increased mouse liver microsome stability and increased necroptosis inhibitory activity could be accomplished by replacement of the 4-cyclopropyl-[1,2,3] thiadiazole with a 5-cyano-1-methylpyrrole. In addition, the SAR and the cellular activity profiles, utilizing different cell types and necroptosis-inducing stimuli, of representative [1,2,3] thiadiazole and pyrrole derivatives were very similar suggesting that the two compound series inhibit necroptosis in the same manner. (C) 2008 Elsevier Ltd. All rights reserved.
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