RESUMEN
To facilitate a drug discovery project, we needed to develop a robust asymmetric synthesis of (2S,5S)-5-substituted-azepane-2-carboxylate derivatives. Two key requirements for the synthesis were flexibility for elaboration at C5 and suitability for large scale preparation. To this end we have successfully developed a scalable asymmetric synthesis of these derivatives that starts with known hydroxy-ketone 8. The key step features an oxidative cleavage of aza-bicyclo[3.2.2]nonene 14, which simultaneously generates the C2 and C5 substituents in a stereoselective manner.
Asunto(s)
Ácidos Carboxílicos/química , Ácidos Carboxílicos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Descubrimiento de Drogas , Cetonas/químicaRESUMEN
The identification of small molecule modulators of biological processes mediated via protein-protein interactions has generally proved to be a challenging endeavor. In the case of the thrombopoietin receptor (TPOr), however, a number of small molecule types have been reported to display biological activity similar to that of the agonist protein TPO. Through a detailed analysis of structure-activity relationships, X-ray crystal structures, NMR coupling constants, nuclear Overhauser effects, and computational data, we have determined the agonism-inducing conformation of one series of small molecule TPOr agonists. The relationship of this agonism-inducing conformation to that of other series of TPO receptor agonists is discussed.
Asunto(s)
Benzamidas/farmacología , Pirimidinas/farmacología , Receptores de Trombopoyetina/agonistas , Trombopoyetina , Animales , Benzamidas/química , Línea Celular , Simulación por Computador , Cristalografía por Rayos X , Espectroscopía de Resonancia Magnética , Unión Proteica , Conformación Proteica , Pirimidinas/química , Receptores de Trombopoyetina/química , Relación Estructura-Actividad , Trombopoyetina/química , Trombopoyetina/metabolismoRESUMEN
Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.
Asunto(s)
Descubrimiento de Drogas , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Isoquinolinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Relación Dosis-Respuesta a Droga , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Isoquinolinas/administración & dosificación , Isoquinolinas/química , Lactamas , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
The acetyl post-translational modification of chromatin at selected histone lysine residues is interpreted by an acetyl-lysine specific interaction with bromodomain reader modules. Here we report the discovery of the potent, acetyl-lysine-competitive, and cell active inhibitor PFI-3 that binds to certain family VIII bromodomains while displaying significant, broader bromodomain family selectivity. The high specificity of PFI-3 for family VIII was achieved through a novel bromodomain binding mode of a phenolic headgroup that led to the unusual displacement of water molecules that are generally retained by most other bromodomain inhibitors reported to date. The medicinal chemistry program that led to PFI-3 from an initial fragment screening hit is described in detail, and additional analogues with differing family VIII bromodomain selectivity profiles are also reported. We also describe the full pharmacological characterization of PFI-3 as a chemical probe, along with phenotypic data on adipocyte and myoblast cell differentiation assays.
Asunto(s)
Compuestos de Azabiciclo/farmacología , Sondas Moleculares/farmacología , Proteínas Nucleares/antagonistas & inhibidores , Piridinas/farmacología , Factores de Transcripción/antagonistas & inhibidores , Compuestos de Azabiciclo/síntesis química , Compuestos de Azabiciclo/química , Cristalografía por Rayos X , Proteínas de Unión al ADN , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Sondas Moleculares/síntesis química , Sondas Moleculares/química , Estructura Molecular , Proteínas Nucleares/metabolismo , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Piridinas/síntesis química , Piridinas/química , Relación Estructura-Actividad , Especificidad por Sustrato , Factores de Transcripción/metabolismoRESUMEN
A synthesis of 4,5-benzo-1-aza-tricyclo[4.3.1.1(3,8)]undecane (1), a benzo-1-aza-adamantane derivative, is described and features a previously unknown application of the Wolff-Kishner reduction of a nonresonance stabilized or "twisted" amide. An intermediate amino ester is converted to a severely "twisted amide", which, when exposed to hydrazine in alcohol, provides the corresponding "twisted" amino hydrazone. Wolff-Kishner conditions (KOH/ethylene glycol, 200 degrees C) provide the reduced target 1 without hydrolysis to amino acid derivatives. These operations are conveniently performed in a single flask in high yield.