ACS Medicinal Chemistry Letters最新文献

Despite the ever-increasinginterest in isoxazole-based compounds,benzo-fused isoxazolidines, or 1,3-dihydro-2,1-benzisoxazoles, arevery rare. Seeking to fill this gap, we present a method for the synthesisof 1,3-dihydro-2,1-benzisoxazoles by intramolecular Cu-mediated orPd-catalyzed C–N coupling of bromoaryl benzylic hydroxylaminederivatives, which can be further derivatized through a simple reductiveamination sequence. This approach overcomes the limitations of previousmethods and provides access to multiple novel heterocyclic scaffolds.As a proof of concept, we apply the method to the synthesis of a benzisoxazolineanalogue of the metabolically labile chiral indane-based MT1/MT2 receptoragonist ramelteon, ultimately furnishing a compound with a >10-foldimprovement in metabolic stability in human hepatocytes. Support forthe bioisosteric nature of the 1,3-dihydro-2,1-benzisoxazole and indanecores was provided in the context of the ramelteon analogue by DFTcalculations.

Skeletal muscle atrophy is driven in part by unrestrainedmyostatin(MSTN) signaling. We designed all-d tripeptide prodrug mimeticsof the MSTN prodomain minimum active 23-mer fragment. Compounds 1 (H-d-Arg-d-Leu-d-Ala-OiPr) and 2 (H-d-Arg-d-Abu-d-Ala-OiPr) inhibitedMSTN-induced myotube atrophy with sub-micromolar potency, while free-acidanalogues (3, 4) and scrambled control (scr) were less active. All-d configuration conferredproteolytic stability exceeding 24 h. In vivo, compound 1 increased soleus mass and grip strength in mice. This work establishescompound 1 as a lead prodrug for MSTN antagonism in muscleatrophy.

Naloxone, naltrexone and nalmefene are closely relatedmorphinanantagonists with comparable affinities to the μ-opioid receptor(MOR) but markedly different pharmacokinetics (PK) and metabolic fate.In this study, we evaluated their pharmacologically-relevant molecular/physicochemicalproperties, PAMPA-BBB (Parallel Artificial Membrane Permeability Assayfor the Blood-Brain Barrier) permeability and in vitro metabolic stabilityto determine how subtle structural differences influence ADME-relevantproperties. Moreover, the pharmacologically-relevant properties ofthese three antagonists were compared with those of the best-knownsynthetic opioid agonist, fentanyl. We found that the methyl-cyclopropylversus allyl head group, as well as the C6-carbonyl versus C6-ethenylgroup, dramatically influence all the above-mentioned properties andhelp explain the in vivo observed differences between these antagonists.These results may support the rational design of new and improvedopioid antagonists with optimized PK properties.

Oxidative stress and xenobiotic exposure disrupt redoxhomeostasisand contribute to neurodegenerative disease progression. The Keap1-Nrf2-AREpathway is a key antioxidant defense mechanism, in which Nrf2 activatescytoprotective gene expression. Because disrupting the Keap1-Nrf2interaction can enhance antioxidant responses, we assessed modifiedCannabis sativa cannabinoids bearing C- and O-β-d-glucosidesas potential Keap1 inhibitors. Building on our earlier fractionationand derivatization work, these compounds were evaluated for bindingto the Keap1 BTB and KDC domains and for activation of Nrf2-mediatedresponses using in vitro and in silico methods. In a Parkinson’s disease model, CS-11 (4a) showed the strongest neuroprotective effect, with an EC₅₀ of 100 nM. Treatment significantly increased cytoprotective geneexpression, indicating enhanced Nrf2 transcriptional activity. CS-11(4a) also restored tyrosine hydroxylase levels and protected dopaminergicneurons from cell death. Computational analyses supported its Keap1-targetingactivity, identifying CS-11 (4a) as a promising Parkinson’sdisease therapeutic candidate.

Rasagiline is a monoamineoxidase B (MAO-B) inhibitorwith neuroprotectiveeffects, whose dependence on MAO-B inhibition remains unclear. Here, indane-to-azaindane rasagiline isosteres (rac-2a and rac-2b) were developedto investigate whether neuroprotection can be decoupled from MAO-Binhibition. Direct regioselective oxidation of 4-azaindane catalyzedby Mn(OAc)₂/^tBuOOH affordedthe key 4-azaindan-1-one intermediate (6a). In paraquat-insulteddopaminergic differentiated SH-SY5Y cells, both analogs showed neuroprotectionat 10 and 100 μM, with rac-2b outperformingrasagiline. The azaindane analogs displayed markedly reduced MAO-Binhibition and no time-dependent inhibition. These findings demonstratethat rasagiline neuroprotection can be dissociated from MAO-B inhibition,supporting azaindane bioisosterism for exploring MAO-independent neuroprotection.

Provided herein are novel compounds as SMARCA2 inhibitors,pharmaceuticalcompositions, use of such compounds in treating non-small cell lungcancer (NSCLE), and processes for preparing such compounds.

Drug-resistant Mycobacterium tuberculosis (Mtb) poses a growing threat, necessitating newtherapeuticstrategies. The cytochrome bcc-aa₃ oxidase (Cyt-bcc) is an attractivetarget, yet single-agent inhibition fails owing to compensation bythe alternative cytochrome bd terminal oxidase (Cyt-bd). Herein, we describe a structure–activity relationship(SAR) study starting from the previously identified Cyt-bd inhibitor 12, leading to the discovery of 17aa (YH-685). YH-685 potently inhibits Cyt-bcc deficient Mycobacterium smegmatis (Δbcc) with a MIC of 0.8 μM and suppresses Cyt-bd dependent oxygen consumption in inverted membrane vesicleswith an IC₅₀ of 0.45 μM. When combined with the Cyt-bcc inhibitor TB47, YH-685 enhanced inhibitionof virulent Mtb H37Rv, reducing both planktonic growthand intracellular bacterial burdens in human macrophages, as assessedby high-content imaging. Under the tested in vitro conditions, this combination achieved growth inhibition comparableto standard regimens rifampicin–isoniazid and bedaquiline.Our study supports co-targeting Cyt-bd and Cyt-bcc as a therapeutic strategy for drug-resistant tuberculosis.