The goal of this R03 proposal is to develop potent, selective antagonists for the orphan receptor GPR17. Ultimately, ligands developed under this application will serve as tools to probe signaling mechanisms and in vivo functions, and could expedite development of novel therapies for diseases potentially mediated by GPR17, such as Multiple Sclerosis (MS). MS is a severe neurological disease characterized by autoimmune-mediated demyelination of neurons and oligodendrocyte damage. The resulting axonal degeneration impairs rapid nerve conduction, which leads to neurological disability if not repaired through remyelination. The remyelination process requires proliferation and maturation of oligodendrocyte precursor cells (OPCs) into myelin producing mature oligodendrocytes. GPR17 is an orphan GPCR that has been identified as a negative regulator of oligodendrocyte maturation and is predominantly expressed in OPCs. GPR17-/- mice have increased CNS myelination and GPR17 overexpressing mice showed lack of myelin sheath formation in the CNS, similar to that seen in myelinating disorders. Addition of the GPR17 agonist probe MDL29,951 to cultures from GPR17+/- mice resulted in reduced differentiation of oligodendrocytes, along with a decrease in myelin basic protein (MBP) and dendrite formation. In addition, studies using an MS mouse model (experimental autoimmune encephalomyelitis, EAE) showed an upregulation of GPR17 in CNS regions where demyelination was occurring. Collectively, these data suggest the involvement of GPR17 in CNS demyelination upon activation. Hence, novel small molecule antagonists that can selectively modulate GPR17 functions will be invaluable tools to study GPR17 biology and lead to new drug discovery opportunities to treat severe demyelinating diseases such as MS. To date, very few small molecule antagonists have been reported in the literature and pharmacological studies with the existing non-selective and less potent antagonists have been challenging. Our preliminary work led to the identification of a novel small molecule lead compound SN-50 (GPR17 IC50 = 1701 nM, CysLT1, IC50 = 6580 nM) through structural modification of Pranlukast, a non-selective GPR17 antagonist (GPR17 IC50 = 588 nM, CysLT1 IC50 = 4 nM). SN-50 exhibited ~3- and 1600-fold reduced potency at GPR17 and CysLT1 respectively, and is ~4-fold selective for GPR17 over CysLT1. Moreover, SN-50 exhibits ~6-fold improved selectivity compared to our previous lead SN-23 (GPR17 IC50 = 1035 nM, CysLT1, IC50 = 590 nM), which promoted oligodendrocyte differentiation upon evaluation in a rat OPC differentiation assay. SN-50 therefore serves as an excellent lead to identify potent and selective GPR17 antagonists.
In Specific Aim 1 of the proposed R03 project, we will synthesize at least 100 novel SN-50 analogs through a series of iterative scaffold modifications.
In Specific Aim 2, we will evaluate the synthesized compounds for GPR17 potency and selectivity over CysLT1. Preliminary ADME properties of two lead compounds with favorable antagonist potency and selectivity (GPR17 IC50 < 100 nM, >50-fold selectivity over CysLT1) will also be evaluated.
These Aims will be accomplished through a collaboration of chemistry and in vitro pharmacology.

Public Health Relevance

This program will provide novel, selective small molecule antagonists of the GPR17 receptor. These compounds will be invaluable tools to study unknown GPR17 biology and lead to new drug discovery opportunities to treat severe demyelinating diseases such as MS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Research Grants (R03)
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Drug Discovery for the Nervous System Study Section (DDNS)
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Utz, Ursula
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Research Triangle Institute
Research Triangle Park
United States
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