Synthesis of Fused Imidazole-Containing Ring Systems via Dual Oxidative Amination of C(sp³)–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⁺ and Ca²⁺ 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