5 research outputs found
Direct Synthesis of <i>N</i>‑Alkyl Arylglycines by Organocatalytic Asymmetric Transfer Hydrogenation of <i>N</i>‑Alkyl Aryl Imino Esters
The organocatalytic
asymmetric transfer hydrogenation of <i>N</i>-alkyl aryl
imino esters for the direct synthesis of <i>N</i>-alkylated
arylglycinate esters is reported. High yields
and enantiomeric ratios were obtained, and tolerance to a diverse
set of functional groups facilitated the preparation of more complex
molecules as well as intermediates for active pharmaceuticals. A simple
recycling protocol was developed for the Brønsted acid catalyst
which could be reused through five cycles with no loss of activity
or selectivity
Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC<sub>2</sub> Agonism and Glucose-Dependent Insulin Secretion
Agonists
of vasoactive intestinal peptide receptor 2 (VPAC<sub>2</sub>) stimulate
glucose-dependent insulin secretion, making them attractive candidates
for the treatment of hyperglycaemia and type-II diabetes. Vasoactive
intestinal peptide (VIP) is an endogenous peptide hormone that potently
agonizes VPAC<sub>2</sub>. However, VIP has a short serum half-life
and poor pharmacokinetics in vivo and is susceptible to proteolytic
degradation, making its development as a therapeutic agent challenging.
Here, we investigated two peptide cyclization strategies, lactamisation
and olefin-metathesis stapling, and their effects on VPAC<sub>2</sub> agonism, peptide secondary structure, protease stability, and cell
membrane permeability. VIP analogues showing significantly enhanced
VPAC<sub>2</sub> agonist potency, glucose-dependent insulin secretion
activity, and increased helical content were discovered; however,
neither cyclization strategy appeared to effect proteolytic stability
or cell permeability of the resulting peptides
Discovery of AZD2716: A Novel Secreted Phospholipase A<sub>2</sub> (sPLA<sub>2</sub>) Inhibitor for the Treatment of Coronary Artery Disease
Expedited
structure-based optimization of the initial fragment hit <b>1</b> led to the design of (<i>R</i>)-<b>7</b> (AZD2716)
a novel, potent secreted phospholipase A<sub>2</sub> (sPLA<sub>2</sub>) inhibitor with excellent preclinical pharmacokinetic properties
across species, clear <i>in vivo</i> efficacy, and minimized
safety risk. Based on accumulated profiling data, (<i>R</i>)-<b>7</b> was selected as a clinical candidate for the treatment
of coronary artery disease
Design of Selective sPLA<sub>2</sub>‑X Inhibitor (−)-2-{2-[Carbamoyl-6-(trifluoromethoxy)‑1<i>H</i>‑indol-1-yl]pyridine-2-yl}propanoic Acid
A lead
generation campaign identified indole-based sPLA<sub>2</sub>-X inhibitors
with a promising selectivity profile against other
sPLA<sub>2</sub> isoforms. Further optimization of sPLA<sub>2</sub> selectivity and metabolic stability resulted in the design of (−)-<b>17</b>, a novel, potent, and selective sPLA<sub>2</sub>-X inhibitor
with an exquisite pharmacokinetic profile characterized by high absorption
and low clearance, and low toxicological risk. Compound (−)-<b>17</b> was tested in an ApoE<sup>–/–</sup> murine
model of atherosclerosis to evaluate the effect of reversible, pharmacological
sPLA<sub>2</sub>-X inhibition on atherosclerosis development. Despite
being well tolerated and achieving adequate systemic exposure of mechanistic
relevance, (−)-<b>17</b> did not significantly affect
circulating lipid and lipoprotein biomarkers and had no effect on
coronary function or histological markers of atherosclerosis
Discovery of a Series of Indole‑2 Carboxamides as Selective Secreted Phospholipase A<sub>2</sub> Type X (sPLA<sub>2</sub>‑X) Inhibitors
In order to assess the potential
of sPLA<sub>2</sub>-X as a therapeutic target for atherosclerosis,
novel sPLA<sub>2</sub> inhibitors with improved type X selectivity
are required. To achieve the objective of identifying such compounds,
we embarked on a lead generation effort that resulted in the identification
of a novel series of indole-2-carboxamides as selective sPLA2-X inhibitors
with excellent potential for further optimization