Optimization of Bicyclic Lactam Derivatives as NMDA Receptor Antagonists

• Published in: ChemMedChem Vol. 12; no. 7; pp. 537 - 545
• Main Authors: Espadinha, Margarida, Dourado, Jorge, Lajarin‐Cuesta, Rocio, Herrera‐Arozamena, Clara, Gonçalves, Lidia M. D., Rodríguez‐Franco, María Isabel, de los Rios, Cristobal, Santos, Maria M. M.
• Format: Journal Article
• Language: English; German
• Published: WEINHEIM Wiley 06.04.2017; Wiley Subscription Services, Inc
• Subjects: Alzheimer Disease - drug therapy; Alzheimer's disease; Animals; Antagonist drugs; antagonists; asymmetric synthesis; bicyclic lactams; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Bridged Bicyclo Compounds - chemistry; Cell Survival - drug effects; Chemistry, Medicinal; Hep G2 Cells; Humans; Lactams - chemistry; Lactams - therapeutic use; Lactams - toxicity; Life Sciences & Biomedicine; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Neuroprotective Agents - chemistry; Neuroprotective Agents - therapeutic use; Neuroprotective Agents - toxicity; nitrogen heterocycles; NMDA receptors; Optimization; Pharmacology & Pharmacy; Rats; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Science & Technology; Structure-Activity Relationship; antagonists; bicyclic lactams; ALZHEIMERS-DISEASE; MODULATORS; NMDA receptors; MEMANTINE; POTENT; asymmetric synthesis; MEMORY; ANTIOXIDANT; GLUTAMATE; nitrogen heterocycles; DRUGS; AGENTS; HYBRIDS
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201700037

N‐Methyl‐d‐aspartate (NMDA) receptors are fundamental for the normal function of the central nervous system (CNS), and play an important role in memory and learning. Over‐activation of these receptors leads to neuronal loss associated with major neurological disorders such as Parkinson's disease, Alzheimer's disease, schizophrenia, and epilepsy. In this study, 22 novel enantiopure bicyclic lactams were designed, synthesized, and evaluated as NMDA receptor antagonists. Most of the new compounds displayed NMDA receptor antagonism, and the most promising compound showed an IC50 value on the same order of magnitude as that of memantine, an NMDA receptor antagonist in clinical use for the treatment of Alzheimer's disease. Further biological evaluation indicated that this compound is brain permeable (determined by an in vitro assay) and non‐hepatotoxic. All these results indicate that (3S,7aS)‐7a‐(4‐chlorophenyl)‐3‐(4‐hydroxybenzyl)tetrahydropyrrolo[2,1‐b]oxazol‐5(6H)‐one (compound 5 b) is a potential candidate for the treatment of pathologies associated with the over‐activation of NMDA receptors. Catch 22: Twenty two novel enantiopure bicyclic lactams were synthesized and evaluated as NMDA receptor antagonists. The most promising compound displayed an IC50 value on the same order of magnitude as that of memantine. In vitro assays indicated that this compound is brain permeable and non‐hepatotoxic; it is a potential candidate for the treatment of pathologies associated with the over‐activation of NMDA receptors.