Technology ID
TAB-3731

Nucleoside Agonists of Adenosine Receptors as Cardio- and Cerebroprotective Agents

E-Numbers
E-022-2019-0
Lead Inventor
Jacobson, Kenneth (NIDDK)
Co-Inventors
Tosh, Dilip (NIDDK)
Reitman, Marc (NIDDK)
Gavrilova, Oksana (NIDDK)
Applications
Therapeutics
Research Materials
Therapeutic Areas
Psychiatry/Mental Health
Ophthalmology
Oncology
Neurology
Infectious Disease
Endocrinology
Dental
Cardiology
Lead IC
NIDDK
ICs
NIDDK
This technology includes a compound for use as a selective agonist of the A1 adenosine receptor (AR) for therapeutic hypothermia and other conditions. We have examined various synthesized nucleosides in a model of mouse hypothermia, in conjunction with AR knockout mice, to characterize the biological profiles. In trying to identify novel highly selective A1AR agonists that have superior in vivo activities, we have adapted a means of rigidifying the ribose moiety of adenosine in the form of a bicyclic (N)-methanocarba ring. We identified and modeled the N6-bicyclobutylmethyl group as a new substituent for the design of A1AR agonists, and peripherally administered compound 9 (MRS7469, containing this group) predominantly activates A1AR in the brain to lower body temperature. In the parallel methanocarba series, enhancement of A1AR affinity and selectivity was found with an alternative nucleobase, which opens the field for more broad synthesis of atypical A1AR agonists.
Commercial Applications
These compounds could potentially be used for therapeutic hypothermia (i.e., to protect the brain in cases of cardiac arrest or stroke). There is also potential for their use in chronic pain, diabetes, cardiac arrhythmias, myocardial infarction, depression and brain ischemia.

Competitive Advantages
Compound is bioavailable and drug-like, with no evident toxicity or potent off-target effects.
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