RESUMEN
Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.
RESUMEN
JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.
RESUMEN
SAR studies of pyrrolo[1,2-f]triazines as JAK2 inhibitors is presented. Achieving JAK2 inhibition selectively over JAK3 is discussed.
Asunto(s)
Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Janus Quinasa 2/metabolismo , Janus Quinasa 3/metabolismo , Pirrolidinas/síntesis química , Triazinas/síntesis química , Triazinas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Janus Quinasa 2/antagonistas & inhibidores , Modelos Moleculares , Estructura Molecular , Unión Proteica , Pirroles/síntesis química , Pirroles/química , Pirroles/farmacología , Pirrolidinas/química , Pirrolidinas/farmacología , Relación Estructura-Actividad , Triazinas/químicaRESUMEN
A short synthesis of the natural product epi-citreodiol and the method developed to gain access to this target are described. Key advances focus on silyl substituted allenes. Upon exposure to dimethyldioxirane, spirodiepoxides form with high face selectivity and subsequently react at the silyl terminus.
Asunto(s)
Compuestos Epoxi/química , Compuestos de Espiro/química , Modelos Moleculares , Conformación Molecular , Estereoisomerismo , Especificidad por SustratoRESUMEN
Three closely related analogues of epoxomicin have been synthesized. Allene-derived spirodiepoxides were key intermediates. Spirodiepoxide formation and stereochemical dependence on solvent, oxidant, and allene structure were cataloged. The facial selectivity of the first epoxidation of 1,3-disubstituted and trisubstituted allenes was found to be >20:1 with dimethyldioxirane in chloroform. For stereogenic allenes, the facial selectivity of the second oxidation is dependent primarily on allene structure and secondarily on solvent and oxidant. For the acyclic systems evaluated this ratio was as high as 8:1. A conformational model is advanced to account for these observations.
Asunto(s)
Compuestos de Espiro/química , Modelos Químicos , Estructura Molecular , Oligopéptidos/síntesis química , Oligopéptidos/química , EstereoisomerismoRESUMEN
Compounds containing a 5-carbamoyl-8-fluoro-3-amino-3,4-dihydro-2H-1-benzopyran and a 3-alkylindole moiety linked through a common basic nitrogen were prepared and evaluated for 5-HT1A affinity, serotonin rat transporter affinity, and functional antagonist activity in vitro. 26a was found to be the most potent and selective compound in this series and was shown to possess neurochemical activity in vivo by producing acute and rapid increases in 5-HT in the rat frontal cortex.
