Increased rigidity and bioisosteric replacement in the design, synthesis and preliminary evaluation of novel, functionalized 3,3-dialkyl- γ-butyrolactones as sigma-2 ligands

AbstractThe sigma-2 ( σ2) receptor has been linked to several diseases and conditions including cancer, neuropathic drug addiction, Alzheimer ’s disease, Parkinson’s disease, traumatic brain injury, Niemann-Pick disease, schizophrenia, depression, and anxiety. Targeting σ2 as a means of treating these diseases and conditions has been the subject of intense research, and several clinical trials have been launched to determine the real-world therapeutic utility of this target. Herein, we report the identification of a novel, semirigid series of functionalized 3,3-dialkyl- γ-butyrolactone σ2 ligands, containing piperazine bioisosteres. The compounds were evaluated using a variety of in vitro assays to determine affinity for sigma receptors, σ1/σ2 selectivity profiles, aqueous solubility, and mouse liver microsome stability.
Source: Medicinal Chemistry Research - Category: Chemistry Source Type: research