ABSTRACT
The pandemic of coronavirus disease 2019 (COVID-19) has urgently necessitated the development of antiviral agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The 3C-like protease (3CLpro) is a promising target for COVID-19 treatment. Here, we report the new class of covalent inhibitors for 3CLpro possessing chlorofluoroacetamide (CFA) as a cysteine reactive warhead. Based on the aza-peptide scaffold, we synthesized the series of CFA derivatives in enantiopure form and evaluated their biochemical efficiencies. The data revealed that 8a (YH-6) with R configuration at the CFA unit strongly blocks the SARS-CoV-2 replication in the infected cells and this potency is comparable to that of nirmatrelvir. The X-ray structural analysis shows that 8a (YH-6) forms a covalent bond with Cys145 at the catalytic center of 3CLpro. The strong antiviral activity and sufficient pharmacokinetics property of 8a (YH-6) suggest its potential as a lead compound for treatment of COVID-19.
ABSTRACT
INTRODUCTION: The aim of this study was to evaluate a newly reported positron emission tomography (PET) radioligand [(11)C]MP-10, a potent and selective inhibitor of the central phosphodiesterase 10A enzyme (PDE10A) in vivo, using PET. METHODS: A procedure was developed for labeling MP-10 with carbon-11. [(11)C]MP-10 was evaluated in vivo both in the pig and baboon brain. RESULTS: Alkylation of the corresponding desmethyl compound with [(11)C]methyl iodide produced [(11)C]MP-10 with good radiochemical yield and specific activity. PET studies in the pig showed that [(11)C]MP-10 rapidly entered the brain reaching peak tissue concentration at 1-2 min postadministration, followed by washout from the tissue. Administration of a selective PDE10A inhibitor reduced the binding in all brain regions to the levels of the cerebellum, demonstrating the saturability and selectivity of [(11)C]MP-10 binding. In the nonhuman primate, the brain tissue kinetics of [(11)C]MP-10 were slower, reaching peak tissue concentrations at 30-60 min postadministration. In both species, the observed rank order of regional brain signal was striatum>diencephalon>cortical regions=cerebellum, consistent with the known distribution and concentration of PDE10A. [(11)C]MP-10 brain kinetics were well described by a two-tissue compartment model, and estimates of total volume of distribution (V(T)) were obtained. Blocking studies with unlabeled MP-10 revealed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential (BP(ND)) as the outcome measure of specific binding. Quantification of [(11)C]MP-10 binding using the simplified reference tissue model with cerebellar input function produced BP(ND) estimates consistent with those obtained by the two-tissue compartment model. CONCLUSION: We demonstrated that [(11)C]MP-10 possesses good characteristics for the in vivo quantification of the PDE10A in the brain by PET.
