Mild and Regioselective <i>N</i>‑Alkylation of 2‑Pyridones in Water

A mild and regioselective <i>N</i>-alkylation reaction of 2-pyridones in water has been developed. Tween 20 (2% w/w) was added to create a micellar system for improved solubility of starting materials, which leads to enhanced reaction rates. The protocol demonstrated a wide substrate scope with good isolated yields (40–94%) for all of the 24 examples evaluated. High regioselectivity favoring <i>N</i>-alkylation over <i>O</i>-alkylation was observed for benzyl halides (>5:1), primary alkyl halides (>6:1), and bulky and less reactive secondary alkyl halides (>2.4:1)

Pro-Formal: políticas y opciones regulatorias para reconocer e integrar mejor el sector doméstico de la madera en los países tropicales

CXCR2 has emerged as a therapeutic target for not only peripheral inflammatory diseases but also neurological abnormalities in the central nervous system (CNS). Herein, we describe the discovery of a novel 1-cyclopentenyl-3-phenylurea series as potent and CNS penetrant CXCR2 antagonists. Extensive SAR studies, wherein molecules’ property forecast index (PFI) was carefully optimized for overall balanced developability profiles, led to the discovery of the advanced lead compound <b>68</b> with a desirable PFI. Compound <b>68</b> demonstrated good in vitro pharmacology with excellent selectivity over CXCR1 and other chemokine receptors. Rat and dog pharmacokinetics (PK) revealed good oral bioavailability, high oral exposure, and desirable elimination half-life of the compound in both species. In addition, the compound demonstrated dose-dependent efficacy in the in vivo pharmacology neutrophil infiltration “air pouch” model in rodents after oral administration. Further, compound <b>68</b> is a CNS penetrant molecule with high unbound fraction in brain tissue

Discovery of CNS Penetrant CXCR2 Antagonists for the Potential Treatment of CNS Demyelinating Disorders

Structure–activity relationship exploration of the historical biarylurea series led to the identification of novel CNS penetrant CXCR2 antagonists with nanomolar potency, favorable PK profile, and good developability potentials. More importantly, the key compound <b>22</b> showed efficacy in a cuprizone-induced demyelination model with twice daily oral administration, thereby supporting CXCR2 to be a potential therapeutic target for the treatment of demyelinating diseases such as multiple sclerosis