6 research outputs found
Synthesis of Fused Imidazole-Containing Ring Systems via Dual Oxidative Amination of C(sp<sup>3</sup>)–H Bonds
A general and efficient
method for a metal-free one-pot synthesis
of highly substituted fused imidazole-containing 5,5- and 5,6-fused
bicyclic heterocycles is described. Starting from commercially available
substrates and reagents, the reaction proceeds through two C–N
bond formations and an oxidative dehydrogenation to form highly substituted
products in good to excellent yield
Step-Economic Synthesis of (+)-Crocacin C: A Concise Crotylboronation/[3,3]-Sigmatropic Rearrangement Approach
The step-economic total synthesis of (+)-crocacin C has
been achieved
in 20% yield from commercially available starting materials. This
approach requires the isolation of only 8 intermediates and can provide
a reliable supply of (+)-crocacin C for the development of new antifungal
and crop protection agents
Leveraging the Pre-DFG Residue Thr-406 To Obtain High Kinase Selectivity in an Aminopyrazole-Type PAK1 Inhibitor Series
To increase kinase selectivity in
an aminopyrazole-based PAK1 inhibitor
series, analogues were designed to interact with the PAK1 deep-front
pocket pre-DFG residue Thr-406, a residue that is hydrophobic in most
kinases. This goal was achieved by installing lactam head groups to
the aminopyrazole hinge binding moiety. The corresponding analogues
represent the most kinase selective ATP-competitive Group I PAK inhibitors
described to date. Hydrogen bonding with the Thr-406 side chain was
demonstrated by X-ray crystallography, and inhibitory activities,
particularly against kinases with hydrophobic pre-DFG residues, were
mitigated. Leveraging hydrogen bonding side chain interactions with
polar pre-DFG residues is unprecedented, and similar strategies should
be applicable to other appropriate kinases
Scaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant <i>N</i>‑(1<i>H</i>‑Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12)
Recent data suggest that inhibition
of dual leucine zipper kinase
(DLK, MAP3K12) has therapeutic potential for treatment of a number
of indications ranging from acute neuronal injury to chronic neurodegenerative
disease. Thus, high demand exists for selective small molecule DLK
inhibitors with favorable drug-like properties and good CNS penetration.
Herein we describe a shape-based scaffold hopping approach to convert
pyrimidine <b>1</b> to a pyrazole core with improved physicochemical
properties. We also present the first crystal structures of DLK. By
utilizing a combination of property and structure-based design, we
identified inhibitor <b>11</b>, a potent, selective, and brain-penetrant
inhibitor of DLK with activity in an in vivo nerve injury model
Structure-Guided Design of Group I Selective p21-Activated Kinase Inhibitors
The
p21-activated kinases (PAKs) play important roles in cytoskeletal
organization, cellular morphogenesis, and survival and have generated
significant attention as potential therapeutic targets for cancer.
Following a high-throughput screen, we identified an aminopyrazole
scaffold-based series that was optimized to yield group I selective
PAK inhibitors. A structure-based design effort aimed at targeting
the ribose pocket for both potency and selectivity led to much-improved
group I vs II selectivity. Early lead compounds contained a basic
primary amine, which was found to be a major metabolic soft spot with
in vivo clearance proceeding predominantly via <i>N</i>-acetylation.
We succeeded in identifying replacements with improved metabolic stability,
leading to compounds with lower in vivo rodent clearance and excellent
group I PAK selectivity
Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design
The <i>N</i>-methyl-d-aspartate receptor (NMDAR)
is a Na<sup>+</sup> and Ca<sup>2+</sup> permeable ionotropic glutamate
receptor that is activated by the coagonists glycine and glutamate.
NMDARs are critical to synaptic signaling and plasticity, and their
dysfunction has been implicated in a number of neurological disorders,
including schizophrenia, depression, and Alzheimer’s disease.
Herein we describe the discovery of potent GluN2A-selective NMDAR
positive allosteric modulators (PAMs) starting from a high-throughput
screening hit. Using structure-based design, we sought to increase
potency at the GluN2A subtype, while improving selectivity against
related α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
receptors (AMPARs). The structure–activity relationship of
channel deactivation kinetics was studied using a combination of electrophysiology
and protein crystallography. Effective incorporation of these strategies
resulted in the discovery of GNE-0723 (<b>46</b>), a highly
potent and brain penetrant GluN2A-selective NMDAR PAM suitable for <i>in vivo</i> characterization