Novel Series of Dihydropyridinone P2X7 Receptor Antagonists

Identification of singleton P2X7 inhibitor <b>1</b> from HTS gave a pharmacophore that eventually turned into potential clinical candidates <b>17</b> and <b>19</b>. During development, a number of issues were successfully addressed, such as metabolic stability, plasma stability, GSH adduct formation, and aniline mutagenicity. Thus, careful modification of the molecule, such as conversion of the 1,4-dihydropyridinone to the 1,2-dihydropyridinone system, proper substitution at C-5″, and in some cases addition of fluorine atoms to the aniline ring allowed for the identification of a novel class of potent P2X7 inhibitors suitable for evaluating the role of P2X7 in inflammatory, immune, neurologic, or musculoskeletal disorders

Novel Series of Dihydropyridinone P2X7 Receptor Antagonists

Identification of singleton P2X7 inhibitor <b>1</b> from HTS gave a pharmacophore that eventually turned into potential clinical candidates <b>17</b> and <b>19</b>. During development, a number of issues were successfully addressed, such as metabolic stability, plasma stability, GSH adduct formation, and aniline mutagenicity. Thus, careful modification of the molecule, such as conversion of the 1,4-dihydropyridinone to the 1,2-dihydropyridinone system, proper substitution at C-5″, and in some cases addition of fluorine atoms to the aniline ring allowed for the identification of a novel class of potent P2X7 inhibitors suitable for evaluating the role of P2X7 in inflammatory, immune, neurologic, or musculoskeletal disorders

Enhanced charge collection in MOF-525-PEDOT nanotube composites enable highly sensitive biosensing

[[abstract]]With the aim of a reliable biosensing exhibiting enhanced sensitivity and selectivity, this study demonstrates a dopamine (DA) sensor composed of conductive poly(3,4-ethylenedioxythiophene) nanotubes (PEDOT NTs) conformally coated with porphyrin-based metal-organic framework nanocrystals (MOF-525). The MOF-525 serves as an electrocatalytic surface, while the PEDOT NTs act as a charge collector to rapidly transport the electron from MOF nanocrystals. Bundles of these particles form a conductive interpenetrating network film that together: (i) improves charge transport pathways between the MOF-525 regions and (ii) increases the electrochemical active sites of the film. The electrocatalytic response is measured by cyclic voltammetry and differential pulse voltammetry techniques, where the linear concentration range of DA detection is estimated to be 2 × 10-6-270 × 10-6m and the detection limit is estimated to be 0.04 × 10-6m with high selectivity toward DA. Additionally, a real-time determination of DA released from living rat pheochromocytoma cells is realized. The combination of MOF5-25 and PEDOT NTs creates a new generation of porous electrodes for highly efficient electrochemical biosensing

Discovery of a Potent (4<i>R</i>,5<i>S</i>)‑4-Fluoro-5-methylproline Sulfonamide Transient Receptor Potential Ankyrin 1 Antagonist and Its Methylene Phosphate Prodrug Guided by Molecular Modeling

Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel expressed in sensory neurons where it functions as an irritant sensor for a plethora of electrophilic compounds and is implicated in pain, itch, and respiratory disease. To study its function in various disease contexts, we sought to identify novel, potent, and selective small-molecule TRPA1 antagonists. Herein we describe the evolution of an <i>N</i>-isopropylglycine sulfonamide lead (<b>1</b>) to a novel and potent (4<i>R</i>,5<i>S</i>)-4-fluoro-5-methylproline sulfonamide series of inhibitors. Molecular modeling was utilized to derive low-energy three-dimensional conformations to guide ligand design. This effort led to compound <b>20</b>, which possessed a balanced combination of potency and metabolic stability but poor solubility that ultimately limited <i>in vivo</i> exposure. To improve solubility and <i>in vivo</i> exposure, we developed methylene phosphate prodrug <b>22</b>, which demonstrated superior oral exposure and robust <i>in vivo</i> target engagement in a rat model of AITC-induced pain