R-7050

EC50: 0.631 μM by TNF-α by ICAM-1 ELISA assay

R-7050 is a TNF-α receptor signaling antagonist.

TNF-α induces biological activity throgh stimulation of the tumor necrosis factor receptor. Although plenty of pre-clinical and clinical evidence suggests a detrimental role, small molecule TNF-αsignaling pathway inhibitors remain largely unexplored in the context of a brain hemorrhage.

In vitro: R-7050 was identified as a selective inhibitot of TNF-α induced cellular signaling by using differential library screening. Unlike biologic TNF inhibitors directly binding TNF-α, R-7050 could not affect binding of TNF-α to TNFR. In contrast, R-7050 was able to selectively inhibit the association of TNF receptor with intracellular adaptor molecules [1].

In vivo: In previous animal study, R-7050 was tested to attenuate neurovascular injury after Intracerebral hemorrhage (ICH) in mice. Results showed that up to 2h post-injury administration of R-7050 was able to significantly reduce blood-brain barrier opening and attenuate edema development at 24h post-ICH. In addition, neurological outcomes were also improved over the first 3 days after injury. Whereas, R-7050 was not found to be albe to reduce hematoma volume, indicating the beneficial effects of TNFR inhibition were downstream of clot formation/resolution [2].

Clinical trial: Up to now, R-7050 is still in the preclinical development stage.

References:
[1] Gururaja TL, Yung S, Ding R, Huang J, Zhou X, McLaughlin J, Daniel-Issakani S, Singh R, Cooper RD, Payan DG, Masuda ES, Kinoshita T.  A class of small molecules that inhibit TNFalpha-induced survival and death pathways via prevention of interactions between TNFalphaRI, TRADD, and RIP1. Chem Biol. 2007 Oct;14(10):1105-18.
[2] King MD, Alleyne CH Jr, Dhandapani KM.  TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice. Neurosci Lett. 2013 May 10;542:92-6.