Session: Posters:

The dihydroquinoline-pyrazoline (DQP) scaffold is a novel class of negative allosteric modulators of the N-methyl-D-aspartate receptors (NMDARs) which displays subunit-selectivity for GluN2C/D over GluN2A/B NMDARs, making them promising therapeutic candidates for several neurological disorders, including epilepsy, Alzheimer's disease, Parkinson's disease, depression, and schizophrenia. From a previous SAR study in our lab, a highly potent compound, EU997-74, was identified with 50 nanomolar activity against GluN2D-subunit and 220-fold selectivity for GluN2D over GluN2A/B. Despite the promising potency and selectivity, low blood-brain barrier (BBB) permeability limits the further exploration of these compounds in vivo. To improve the CNS druglike properties of the EU997 series, multiple strategies were explored. To this end, a series of analogs to investigate SAR of C rings, pyrazoline ring, terminal acid was designed, synthesized, and evaluated the activity for NMDARs.

Stephen Traynelis

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