5 research outputs found
Palladium-Catalyzed Ī±āArylation of Sultams with Aryl and Heteroaryl Iodides
PalladiumĀ(0)-catalyzed conditions
for the Ī±-arylation of
sultams with aryl and heteroaryl iodides have been developed. Arylation
of 3-substituted 1,3-propanesultams gave rise to high yields and high
diastereomeric ratios, leading to the thermodynamically favored <i>cis</i> product. The arylation was broadly applicable to various
electron-rich and electron-poor (hetero)Āaromatic iodides
Experimental and Computational Studies of the Diastereoselective Alkylations of 3āSubstituted Ī³āSultams
We
report that chiral 3-substituted Ī³-sultam Ī±-carbanions
undergo diastereoselective alkylation reactions with alkyl halides
to predominantly produce <i>trans</i>-3,5-disubstituted
Ī³-sultam products. Quantum mechanical calculations provided
a stereoelectronic rationale for the observed diastereoselectivity
Palladium-Catalyzed Ring Expansion of Spirocyclopropanes to Form Caprolactams and Azepanes
A palladium(0)-catalyzed
rearrangement of piperidones and piperidines
bearing a spirocyclopropane ring was developed. The ring expansion
reaction led to a variety of functionalized caprolactam and azepane
products in good to excellent yields. Experimental and computational
mechanistic studies revealed an initial oxidative addition of the
distal carbonācarbon bond of a cyclopropane ring to the palladium(0)
catalyst and the relief of ring strain as a driving force for product
formation
Discovery of 1ā{4-[3-Fluoro-4-((3<i>S</i>,6<i>R</i>)ā3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone (GNE-3500): a Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C (RORc or RORĪ³) Inverse Agonist
Retinoic
acid receptor-related orphan receptor C (RORc, RORĪ³, or NR1F3)
is a nuclear receptor that plays a major role in the production of
interleukin (IL)-17. Considerable efforts have been directed toward
the discovery of selective RORc inverse agonists as potential treatments
of inflammatory diseases such as psoriasis and rheumatoid arthritis.
Using the previously reported tertiary sulfonamide <b>1</b> as
a starting point, we engineered structural modifications that significantly
improved human and rat metabolic stabilities while maintaining a potent
and highly selective RORc inverse agonist profile. The most advanced
Ī“-sultam compound, GNE-3500 (<b>27</b>, 1-{4-[3-fluoro-4-((3<i>S</i>,6<i>R</i>)-3-methyl-1,1-dioxo-6-phenyl-[1,2]Āthiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone),
possessed favorable RORc cellular potency with 75-fold selectivity
for RORc over other ROR family members and >200-fold selectivity
over 25 additional nuclear receptors in a cell assay panel. The favorable
potency, selectivity, in vitro ADME properties, in vivo PK, and dose-dependent
inhibition of IL-17 in a PK/PD model support the evaluation of <b>27</b> in preclinical studies
Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice
A series
of trisubstituted hydroxylactams was identified as potent
enzymatic and cellular inhibitors of human lactate dehydrogenase A.
Utilizing structure-based design and physical property optimization,
multiple inhibitors were discovered with <10 Ī¼M lactate IC<sub>50</sub> in a MiaPaca2 cell line. Optimization of the series led
to <b>29</b>, a potent cell active molecule (MiaPaca2 IC<sub>50</sub> = 0.67 Ī¼M) that also possessed good exposure when
dosed orally to mice