Discovery, Synthesis, and Preclinical Characterization of <i>N</i>‑(3-Chloro-4-fluorophenyl)‑1<i>H</i>‑pyrazolo[4,3‑<i>b</i>]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu₄)

The efficacy of positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 4 (mGlu₄) in preclinical rodent models of Parkinson’s disease has been established by a number of groups. Here, we report an advanced preclinically characterized mGlu₄ PAM, <i>N</i>-(3-chloro-4-fluorophenyl)-1<i>H</i>-pyrazolo­[4,3-<i>b</i>]­pyridin-3-amine (VU0418506). We detail the discovery of VU0418506 starting from a common picolinamide core scaffold and evaluation of a number of amide bioisosteres leading to the novel pyrazolo­[4,3-<i>b</i>]­pyridine head group. VU0418506 has been characterized as a potent and selective mGlu₄ PAM with suitable in vivo pharmacokinetic properties in three preclinical safety species

Discovery of Potent 2‑Aryl-6,7-dihydro‑5<i>H</i>‑pyrrolo[1,2‑<i>a</i>]imidazoles as WDR5-WIN-Site Inhibitors Using Fragment-Based Methods and Structure-Based Design

WDR5 is a chromatin-regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed-lineage leukemia. Here, we describe the discovery of potent and selective WDR5-WIN-site inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified several chemically distinct hit series that bind to the WIN site within WDR5. Members of a 6,7-dihydro-5<i>H</i>-pyrrolo­[1,2-<i>a</i>]­imidazole fragment class were expanded using a structure-based design approach to arrive at lead compounds with dissociation constants <10 nM and micromolar cellular activity against an AML-leukemia cell line. These compounds represent starting points for the discovery of clinically useful WDR5 inhibitors for the treatment of cancer

Discovery of Potent 2‑Aryl-6,7-dihydro‑5<i>H</i>‑pyrrolo[1,2‑<i>a</i>]imidazoles as WDR5-WIN-Site Inhibitors Using Fragment-Based Methods and Structure-Based Design

WDR5 is a chromatin-regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed-lineage leukemia. Here, we describe the discovery of potent and selective WDR5-WIN-site inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified several chemically distinct hit series that bind to the WIN site within WDR5. Members of a 6,7-dihydro-5<i>H</i>-pyrrolo­[1,2-<i>a</i>]­imidazole fragment class were expanded using a structure-based design approach to arrive at lead compounds with dissociation constants <10 nM and micromolar cellular activity against an AML-leukemia cell line. These compounds represent starting points for the discovery of clinically useful WDR5 inhibitors for the treatment of cancer