3 research outputs found
Systematic Study of the Glutathione (GSH) Reactivity of <i>N</i>‑Arylacrylamides: 1. Effects of Aryl Substitution
Success
in the design of targeted covalent inhibitors depends in
part on a knowledge of the factors influencing electrophile reactivity.
In an effort to further develop an understanding of structure–reactivity
relationships among <i>N</i>-arylacrylamides, we determined
glutathione (GSH) reaction rates for a family of <i>N</i>-arylacrylamides independently substituted at ortho-, meta-, and
para-positions with 11 different groups common to inhibitor design.
We find that substituent effects on reaction rates show a linear Hammett
correlation for ortho-, meta-, and para-substitution. In addition,
we note a correlation between <sup>1</sup>H and <sup>13</sup>C NMR
chemical shifts of the acrylamide with GSH reaction rates, suggesting
that NMR chemical shifts may be a convenient surrogate measure of
relative acrylamide reactivity. Density functional theory calculations
reveal a correlation between computed activation parameters and experimentally
determined reaction rates, validating the use of such methodology
for the screening of synthetic candidates in a prospective fashion
Discovery, Optimization, and in Vivo Evaluation of Benzimidazole Derivatives AM-8508 and AM-9635 as Potent and Selective PI3Kδ Inhibitors
Lead
optimization efforts resulted in the discovery of two potent,
selective, and orally bioavailable PI3Kδ inhibitors, <b>1</b> (AM-8508) and <b>2</b> (AM-9635), with good pharmacokinetic
properties. The compounds inhibit B cell receptor (BCR)-mediated AKT
phosphorylation (pAKT) in PI3Kδ-dependent in vitro cell based
assays. These compounds which share a benzimidazole bicycle are effective
when administered in vivo at unbound concentrations consistent with
their in vitro cell potency as a consequence of improved unbound drug
concentration with lower unbound clearance. Furthermore, the compounds
demonstrated efficacy in a Keyhole Limpet Hemocyanin (KLH) study in
rats, where the blockade of PI3Kδ activity by inbibitors <b>1</b> and <b>2</b> led to effective inhibition of antigen-specific
IgG and IgM formation after immunization with KLH
Discovery and in Vivo Evaluation of the Potent and Selective PI3Kδ Inhibitors 2‑((1<i>S</i>)‑1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro‑<i>N</i>‑methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-0687) and 2‑((1<i>S</i>)‑1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-5-fluoro‑<i>N</i>‑methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-1430)
Optimization
of the potency and pharmacokinetic profile of 2,3,4-trisubstituted
quinoline, <b>4</b>, led to the discovery of two potent, selective,
and orally bioavailable PI3Kδ inhibitors, <b>6a</b> (AM-0687)
and <b>7</b> (AM-1430). On the basis of their improved profile,
these analogs were selected for in vivo pharmacodynamic (PD) and efficacy
experiments in animal models of inflammation. The in vivo PD studies,
which were carried out in a mouse pAKT inhibition animal model, confirmed
the observed potency of <b>6a</b> and <b>7</b> in biochemical
and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin
model in rats demonstrated that administration of either <b>6a</b> or <b>7</b> resulted in a strong dose-dependent reduction
of IgG and IgM specific antibodies. The excellent in vitro and in
vivo profiles of these analogs make them suitable for further development