3 research outputs found
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: polĂticas y opciones regulatorias para reconocer e integrar mejor el sector domĂ©stico de la madera en los paĂses 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