Dr. Sinha’s research focuses on synthetic medicinal chemistry and chemical biology of neurological disorders, including Alzheimer’s disease, Parkinson’s disease, and major depressive disorder. In the United States alone, more than 5.2 million people live with Alzheimer’s, 500,000 live with Parkinson’s, and nearly 14.8 million adults are affected by major depressive disorder in a given year. Dr. Sinha is interested in developing both natural and non-natural products as tools and therapies for analyzing, detecting, and treating these disorders.
Accumulation of amyloid-β peptides, mainly Aβ-42, in the Alzheimer’s brain is most likely a prime cause of the disease. In recent years, Dr. Sinha has focused on a series of “hit” compounds that interfere with amyloid-β production and accumulation for “hit-to-lead” development. Two hit compounds are a kinase inhibitor and an inactive analog of another kinase inhibitor. Among more than 300 new analogs of these hit compounds examined, half a dozen were identified as inhibiting amyloid-β peptides production/secretion as potently as the hit compounds, but with superior brain permeability. These compounds are undergoing in vivo studies using Alzheimer’s mouse models to determine the therapeutic efficacies. The third hit compound, a Notch-sparing potent γ-secretase inhibitor, compound 122, was obtained from a Chinese medicinal plant, Ligustrum lucidum. Among more than 60 new analogs of compound 122 examined, at least six are multiple-fold more potent and suitable for in vivo evaluation.
Dr. Sinha and colleagues are also developing modulatory small molecules for other important targets, such as phosphorylation-related enzymes and receptors relevant for central nervous system diseases. There are vast opportunities in these areas for understanding enzyme functions and for drug development. Similarly, they are exploring the possibility of selective, effective treatment of central nervous system disorders using G protein-coupled receptors.