Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer’s Disease

Significant data exists to suggest that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator of neuronal degeneration following neuronal injury and in chronic neurodegenerative disease. Consequently, there is considerable interest in the identification of DLK inhibitors with a profile compatible with development for these indications. Herein, we use structure-based drug design combined with a focus on CNS drug-like properties to generate compounds with superior kinase selectivity and metabolic stability as compared to previously disclosed DLK inhibitors. These compounds, exemplified by inhibitor <b>14</b>, retain excellent CNS penetration and are well tolerated following multiple days of dosing at concentrations that exceed those required for DLK inhibition in the brain

Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer’s Disease

Significant data exists to suggest that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator of neuronal degeneration following neuronal injury and in chronic neurodegenerative disease. Consequently, there is considerable interest in the identification of DLK inhibitors with a profile compatible with development for these indications. Herein, we use structure-based drug design combined with a focus on CNS drug-like properties to generate compounds with superior kinase selectivity and metabolic stability as compared to previously disclosed DLK inhibitors. These compounds, exemplified by inhibitor <b>14</b>, retain excellent CNS penetration and are well tolerated following multiple days of dosing at concentrations that exceed those required for DLK inhibition in the brain

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

Discovery of Potent and Selective Pyrazolopyrimidine Janus Kinase 2 Inhibitors

The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo­[1,5-<i>a</i>]­pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds <b>7a</b>–<b>b</b> and <b>8</b> in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of <b>7j</b>. In a SET2 xenograft model that is dependent on Jak2 for growth, <b>7j</b> demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2

Discovery of 7‑Tetrahydropyran-2-yl Chromans: β‑Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors That Reduce Amyloid β‑Protein (Aβ) in the Central Nervous System

In an attempt to increase selectivity vs Cathepsin D (CatD) in our BACE1 program, a series of 1,3,4,4a,10,10a-hexahydropyrano­[4,3-b]­chromene analogues was developed. Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Using structure-based design, substitutions to improve binding to both the S3 and S2′ sites of BACE1 were explored. An acyl guanidine moiety provided the most potent analogues. These compounds demonstrated 10–420 fold selectivity for BACE1 vs CatD, and were highly potent in a cell assay measuring Aβ_1–40 production (5–99 nM). They also suffered from high efflux. Despite this undesirable property, two of the acyl guanidines achieved free brain concentrations (C_free,brain) in a guinea pig PD model sufficient to cover their cell IC₅₀s. Moreover, a significant reduction of Aβ_1–40 in guinea pig, rat, and cyno CSF (58%, 53%, and 63%, respectively) was observed for compound <b>62</b>