Journal of Medicinal Chemistry最新文献

N-Methyl-d-aspartate receptors are ionotropic glutamate receptors that mediate fast excitatory neurotransmission in the central nervous system. These receptors play essential roles in synaptic plasticity, learning, and memory and are implicated in various neuropathological and psychiatric disorders. Selective modulation of NMDAR subtypes, particularly GluN2A, has proven challenging. The TCN-201 derivatives MPX-004 and MPX-007 are potent and selective for GluN2A receptors, yet their physical properties limit their in vivo utility. In this study, we optimized the MPX-004/MPX-007 scaffold by modifying the linker region between the distal halogenated aromatic ring and the central pyrazine nucleus, resulting in the identification of potent and selective compounds with improved drug-like properties. Notably, compound 1 was used to develop the first GluN2A NAM-based radioligand, and compound 11 showed improved pharmacokinetics and dose-dependent receptor occupancy in vivo. Thus, we provide an array of powerful new tools for the study of GluN2A receptors.

CCR6 is a chemokine receptor that mediates the migration of pathogenic inflammatory leukocytes to sites of inflammation in response to its ligand, CCL20. Herein we report the design of a potent CCR6 antagonist capable of inhibiting the chemotactic migration of CCR6⁺ T cells in vitro. Key to this finding was the discovery of a remarkable methyl substituent effect on antagonist potency. A 365-fold improvement in potency was observed for the cis-2-methylcyclohexanamine analogue compared to the unsubstituted cyclohexanamine derivative. Evidence generated through the characterization of conformationally restricted analogues supports the conclusion that the large potency enhancement is the result of the methyl substituent biasing the cyclohexane ring ground state conformation to favor that of the bound ligand and thus decreasing the ligand strain energy.

Histone arginine asymmetric dimethylation, which is mainly catalyzed by type I protein arginine methyltransferases (PRMTs), is involved in broad biological and pathological processes. Recently, several type I PRMT inhibitors, such as MS023, have been developed to reverse the histone arginine dimethylation status in tumor cells, but extensive inhibition of type I PRMTs may cause side effects in normal tissues. Herein, we designed a photoactivatable MS023 prodrug (C-MS023) to achieve spatiotemporal inhibition of histone arginine asymmetric dimethylation. In vitro studies showed that C-MS023 exhibited reduced potency in inhibiting type I PRMTs. Importantly, visible light irradiation at 420 nm could trigger the photolysis of the prodrug, thereby liberating MS023 for effective downregulation of histone arginine asymmetric dimethylation and DNA replication-related transcriptomic activities. This opto-epigenetic small-molecule prodrug potentially aids in further research into the pathophysiological functions of type I PRMTs and the development of targeted epigenetic therapeutics.

Lipophilicity and acid–base properties are two key aspects of the optimization of a compound in drug discovery. Using ¹⁹F NMR, we experimentally determined the log D^7.4 of a wide array of 2-thiofluoroalkyl (SR_F) and 2-sulfonyl fluoroalkyl (SO₂R_F) substituted pyridines and the pK_a values of their protonated counterparts. Statistical modeling based on constitutional and DFT descriptors provided further insights into the structure–property relationship, explaining the experimental observations and predicting log D^7.4 values. Our results highlight the influence of fluorination topology in SR_F fragments and demonstrate the dual effect of fluorine on molecular polarity, increasing the hydrophobic surface and the polarity of the sulfur moiety. By analyzing methyl- and ethyl-derived fragments, we found a gradient in log D^7.4 values influenced by the oxidation state of the sulfur atom and fluorination pattern. Our findings emphasize the context-dependent impact of fluorination and offer insights to better understand the impact of thiofluoroalkyl chains on these physicochemical properties.