RESUMO
Indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme that mediates the rate-limiting step in the metabolism of l-tryptophan to kynurenine, has been widely explored as a potential immunotherapeutic target in oncology. We developed a class of inhibitors with a conformationally constrained bicyclo[3.1.0]hexane core. These potently inhibited IDO1 in a cellular context by binding to the apoenzyme, as elucidated by biochemical characterization and X-ray crystallography. A SKOV3 tumor model was instrumental in differentiating compounds, leading to the identification of IACS-9779 (62) and IACS-70465 (71). IACS-70465 has excellent cellular potency, a robust pharmacodynamic response, and in a human whole blood assay was more potent than linrodostat (BMS-986205). IACS-9779 with a predicted human efficacious once daily dose below 1 mg/kg to sustain >90% inhibition of IDO1 displayed an acceptable safety margin in rodent toxicology and dog cardiovascular studies to support advancement into preclinical safety evaluation for human development.
Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The use of allenes and 1,3-dienes as chiral allylmetal pronucleophiles in intermolecular catalytic enantioselective reductive additions to aldehydes, ketones, imines, carbon dioxide and other C=X electrophiles is exhaustively catalogued together with redox-neutral hydrogen auto-transfer processes. Coverage is limited to processes that result in both C-H and C-C bond formation. The use of alkynes as latent allylmetal pronucleophiles and multicomponent C=X allylations involving allenes and dienes is not covered. As illustrated in this review, the ability of allenes and 1,3-dienes to serve as tractable non-metallic pronucleophiles has evoked many useful transformations that have no counterpart in traditional allylmetal chemistry.
Assuntos
Alcadienos , Alcinos , Catálise , EstereoisomerismoRESUMO
The first catalytic enantioselective ruthenium-catalyzed carbonyl reductive couplings of allene pronucleophiles is described. Using an iodide-modified ruthenium-BINAP-catalyst and O-benzhydryl alkoxyallene 1a, carbonyl (α-alkoxy)allylation occurs from the alcohol or aldehyde oxidation level to form enantiomerically enriched syn-sec,tert-diols. Internal chelation directs intervention of (Z)-σ-alkoxyallylruthenium isomers, which engage in stereospecific carbonyl addition.