RESUMEN
A series of 1,1'-spiro-substituted hexahydrofuroquinoline derivatives exhibiting potent cholesteryl ester transfer protein (CETP) inhibition at reduced lipophilicity was identified. A focused structure-activity relationship (SAR) exploration led to the potent and comparatively polar CETP inhibitor 26 showing robust high density lipoprotein-cholesterol (HDL-C) elevation and low density lipoprotein-cholesterol (LDL-C) reduction in transgenic hCETP/hApoB-100 mice. Compound 26 was also shown to positively differentiate from highly lipophilic CETP inhibitors in its complete elimination from fat tissue in hCETP transgenic mice as evident within 21 days after cessation of treatment. In addition, compound 26 showed no significant effects on aldosterone secretion from H295R cells, as well as no significant effects on blood pressure and electrocardiogram parameters in telemetrized cynomolgus monkeys.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Hidroxiquinolinas/síntesis química , Quinolinas/síntesis química , Compuestos de Espiro/síntesis química , Animales , Anticolesterolemiantes/síntesis química , Anticolesterolemiantes/farmacocinética , Anticolesterolemiantes/farmacología , HDL-Colesterol/sangre , Humanos , Hidroxiquinolinas/farmacocinética , Hidroxiquinolinas/farmacología , Macaca fascicularis , Ratones Transgénicos , Quinolinas/farmacocinética , Quinolinas/farmacología , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
An efficient enantioselective synthesis of the chiral polycyclic cholesteryl ester transfer protein (CETP) inhibitor 1 has been developed. The synthesis was rendered practical for large scale via the development of a modified Hantzsch-type reaction to prepare the sterically hindered pyridine ring, enantioselective hydrogenation of hindered ketone 6 utilizing novel BIBOP-amino-pyridine derived Ru complex, efficient ICl promoted lactone formation, and a BF3 mediated hydrogenation process for diastereoselective lactol reduction. This efficient route was successfully scaled to produce multikilogram quantities of challenging CETP drug candidate 1.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Piridinas/síntesis química , Piridinas/farmacología , Cristalografía por Rayos X , Hidrogenación , Conformación Molecular , Estructura Molecular , Piridinas/química , EstereoisomerismoRESUMEN
Chemistry has been developed to specifically functionalize two structurally similar classes of indole-based MK2 inhibitors at positions prompted by a combination of X-ray crystallographic and computer assisted drug design. A gain in molecular potency was obtained by introducing aminomethyl groups to the lactam rings of 6-arylcarbamoyl-tetrahydro-beta-carbolinone and 6-arylcarbamoyl-dihydropyrazino[1,2-a]indolone MK2 inhibitors. In addition, improvements in molecular potency were achieved by expansion of the lactam from a 6- to 7-membered ring leading to 7-arylcarbamoyl-tetrahydro-[1,4]diazepino[1,2-a]indolones.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Indoles/síntesis química , Indoles/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Indoles/química , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Modelos Moleculares , Estructura Molecular , Proteínas Serina-Treonina Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
The fully functionalised C29-C51 southern hemisphere of altohyrtin A/spongistatin 1 , incorporating the E- and F-ring tetrahydropyran rings and the unsaturated side chain, has been synthesised in a highly convergent and stereocontrolled manner. Key steps in the synthesis of this phosphonium salt include four highly diastereoselective, substrate-controlled, boron aldol reactions to establish key C-C bonds and accompanying stereocentres, where the introduction of the chlorodiene side chain and the C47 hydroxyl-bearing centre were realised by exploiting remote stereoinduction from the F-ring tetrahydropyran.
Asunto(s)
Antineoplásicos/síntesis química , Macrólidos/síntesis química , Acetales/síntesis química , Alcoholes/química , Boro/química , Cinética , Estructura Molecular , Piranos/química , Compuestos de Espiro/síntesis química , Estereoisomerismo , TermodinámicaRESUMEN
As an exceptionally potent antimitotic macrolide, altohyrtin A/spongistatin 1 shows great promise in cancer chemotherapy but its extreme scarcity in the natural sponges has halted its further preclinical development. A highly stereocontrolled total synthesis, which exploits boron-mediated aldol bond constructions, has been realized to provide, for the first time, a useful amount of synthetic material.