RESUMEN
NaV1.7 is an actively pursued, genetically validated, target for pain. Recently reported quinolinone sulfonamide inhibitors displayed promising selectivity profiles as well as efficacy in preclinical pain models; however, concerns about off-target liabilities associated with this series resulted in an effort to reduce the lipophilicity of these compounds. Successful prosecution of this strategy was challenging due to the opposing requirement for lipophilic inhibitors for NaV1.7 potency and in vivo clearance (CL). Deconstruction of the heterocyclic core of the quinolinone series and utilization of an intramolecular hydrogen bond to mimic the requisite pharmacophore enabled the introduction of polarity without adversely impacting CL. Ultimately, this strategy led to the identification of compound 29, which demonstrated favorable ADME and was efficacious in pre-clinical models of pain.
Asunto(s)
Canal de Sodio Activado por Voltaje NAV1.7 , Quinolonas , Humanos , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Dolor/tratamiento farmacológico , Relación Estructura-Actividad , Sulfanilamida , Sulfonamidas/química , Sulfonamidas/farmacología , Urea/farmacología , Bloqueadores del Canal de Sodio Activado por Voltaje/químicaRESUMEN
Overexpression of the antiapoptotic protein Mcl-1 provides a survival advantage to some cancer cells, making inhibition of this protein an attractive therapeutic target for the treatment of certain types of tumors. Herein, we report our efforts toward the identification of a novel series of macrocyclic Mcl-1 inhibitors featuring an α-hydroxy phenylacetic acid pharmacophore or bioisostere. This work led to the discovery of 1, a potent Mcl-1 inhibitor (IC50 = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic properties and excellent in vivo efficacy in an OPM-2 multiple myeloma xenograft model.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Fenilacetatos/química , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Línea Celular Tumoral , Cristalografía por Rayos X , Diseño de Fármacos , Estabilidad de Medicamentos , Femenino , Humanos , Enlace de Hidrógeno , Ratones Desnudos , Mieloma Múltiple/tratamiento farmacológico , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/química , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Treatment of the acetylenic bromoamide 42c, derived from the enantiopure alpha-amino alcohol 40, with Bu(3)SnH-AlBN results in an efficient 5-exo dig radical cyclisation to the 4-methylenepyrrolidinone 43/44 (2:1). Cleavage of the alkene bond in 43/44, using O(3)-Me(2)S, next gave the corresponding 4-ketopyrrolidinone 45/46. Alpha-phenylsulfanylation of 45/46, using S-methyl-p-toluenethiosulfonate-Et(3)N, proceeded in a stereoselective manner and led to the methylsulfanyl derivative 48 (ca. 9:1 selectivity). Manipulation of the functionality in 48, using two separate sequences, then led to the substituted pyrrolidinones 49b, 50 and 53 which are advanced intermediates in a previous synthesis of (+)-lactacystin 1. In related studies, the acetylenic bromoamide 28a containing all the carbon atoms in lactacystin was synthesised, but this substrate failed to undergo an anticipated radical cyclisation to the 4-methylenepyrrolidinone 30, analogous to 43/44. Instead, only the product of reduction of 28a, i.e. 28b, was produced, possibly resulting from adventitious intramolecular hydrogen-abstraction processes from the carbon centred radical intermediate 29, i.e. 32 to 33 and/or 31 to 34.
Asunto(s)
Acetilcisteína/análogos & derivados , Pirrolidinonas/química , Acetilcisteína/síntesis química , Acetilcisteína/química , Ciclización , Radicales Libres/química , Metilación , Estructura Molecular , Serina/química , EstereoisomerismoRESUMEN
A novel synthesis of 3-substituted-3,4-dihydro-2H-1,3-benzothiazin-2-ones is described herein. The strategy relies on a highly regioselective palladium-catalyzed carbonylation of 2-substituted-2,3-dihydro-1,2-benzisothiazoles to give the corresponding 3,4-dihydro-2H-1,3-benzothiazin-2-one derivatives in good to excellent yields.