NU 2014-101

INVENTORS

• Richard Silverman*
• Paramita Mukherjee

SHORT DESCRIPTION

This invention introduces novel 2-imidazolyl-pyrimidine scaffolds that inhibit neuronal nitric oxide synthase. It offers potential for drug development targeting Parkinson’s and other neurodegenerative diseases.

BACKGROUND

Neurodegenerative disorders such as Parkinson’s, Alzheimer’s, and Huntington’s disease lack effective treatment options. Current nNOS inhibitors often suffer from poor oral bioavailability, complex synthesis, and limited selectivity. The industry needs simpler, more efficient compounds to overcome these hurdles.

ABSTRACT

Novel 2-imidazolyl-pyrimidine compounds target neuronal nitric oxide synthase with high selectivity and potency. They work via a unique binding mode that leverages heme-Fe coordination in the enzyme’s active site. The compounds are synthesized in a streamlined six-step process, yielding high-purity material. In vitro assays, including a Caco-2 permeability test, demonstrate promising oral bioavailability and blood-brain barrier penetration. These attributes position the compounds as strong candidates for neurodegenerative therapeutic development.

MARKET OPPORTUNITY

The global market for neurodegenerative disease therapeutics was valued at approximately $45.5 billion in 2023 and is projected to expand at a compound annual growth rate (CAGR) of 8.6% from 2024 to 2032 (Source: Grand View Research, 2023).

DEVELOPMENT STAGE

TRL-4 - Prototype Validated in Lab: Key functions, including synthetic feasibility and biological activity, have been demonstrated in laboratory-scale experiments.

APPLICATIONS

• Prevention or treatment of neurodegenerative diseases: Targets conditions like Parkinson’s, Alzheimer’s, and Huntington’s disease via nNOS inhibition.
• Chemical probes for enzyme studies: Facilitates research into neuronal nitric oxide synthase function and drug development.

ADVANTAGES

• Optimized drug-like properties: Improved physicochemical parameters support oral bioavailability and blood-brain barrier penetration.
• Distinct binding mode: The unique heme-Fe coordination provides selective nNOS inhibition.
• Simplified synthesis: A straightforward six-step process reduces complexity and production costs.
• High selectivity: Demonstrates 100-fold selectivity over off-target receptors and related enzyme isoforms.

PUBLICATIONS

• Richard Silverman et al, Novel 2,4-Disubstituted Pyrimidines as Potent Selective and Cell-Permeable Inhibitors of Neuronal Nitric Oxide Synthase, Journal of Medicinal Chemistry, December 9 2014

IP STATUS

Issued US Patent 9,878,996.

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