RESUMEN
The discovery of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid 13n (ceralifimod, ONO-4641), a sphingosine-1-phosphate (S1P) receptor agonist selective for S1P1 and S1P5, is described. While it has been revealed that the modulation of the S1P1 receptor is an effective way to treat autoimmune diseases such as relapsing-remitting multiple sclerosis (RRMS), it was also reported that activation of the S1P3 receptor is implicated in some undesirable effects. We carried out a structure-activity relationship (SAR) study of hit compound 6 with an amino acid moiety in the hydrophilic head region. Following identification of a lead compound with a dihydronaphthalene central core by inducing conformational constraint, optimization of the lipophilic tail region led to the discovery of 13n as a clinical candidate that exhibited >30â¯000-fold selectivity for S1P1 over S1P3 and was potent in a peripheral lymphocyte lowering (PLL) test in mice (ED50 = 0.029 mg/kg, 24 h after oral dosing).
Asunto(s)
Azetidinas/farmacología , Linfocitos/efectos de los fármacos , Naftalenos/farmacología , Receptores de Lisoesfingolípidos/agonistas , Administración Oral , Animales , Enfermedades Autoinmunes/tratamiento farmacológico , Azetidinas/administración & dosificación , Azetidinas/química , Azetidinas/farmacocinética , Células CHO , Cricetulus , Femenino , Humanos , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos BALB C , Naftalenos/administración & dosificación , Naftalenos/química , Naftalenos/farmacocinética , Ratas Endogámicas Lew , Ratas Sprague-DawleyRESUMEN
Structure-activity relationship (SAR) of sphingosine-1-phosphate receptor agonists with a dihydronaphthalene scaffold was investigated. Compound 1 was modified to improve S1P(1) agonistic activity and in vivo peripheral lymphocyte lowering (PLL) activity without impairing selectivity over S1P(3) agonistic activity. A detailed SAR study of the terminal lipophilic part revealed that the introduction of substituents on the propylene linker and the terminal benzene ring influences in vitro and PLL activities. Compound 6n bearing a (S)-methyl group at the 2-position on the propylene linker and chlorine at the para-position on the terminal benzene ring showed potent hS1P(1) agonistic activity with excellent selectivity over hS1P(3) and in vivo PLL activity in mice.
Asunto(s)
Química Farmacéutica/métodos , Lisofosfolípidos/antagonistas & inhibidores , Naftalenos/química , Receptores de Lisoesfingolípidos/antagonistas & inhibidores , Esfingosina/análogos & derivados , Administración Oral , Animales , Benceno/química , Cloro/química , Diseño de Fármacos , Humanos , Ligandos , Ratones , Modelos Químicos , Ratas , Esfingosina/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Structure-activity relationship of sphingosine-1-phosphate receptor agonists was examined. Cinnamyl derivative 1 was modified to improve S1P(1) agonistic activity as well as selectivity over S1P(3) agonistic activity. Dihydronaphthalene derivative 10d was identified as a potent S1P(1) receptor agonist with high selectivity against S1P(3) and enhanced efficacy in lowering peripheral lymphocyte counts in mice.
Asunto(s)
Naftalenos/síntesis química , Propanoles/química , Receptores de Lisoesfingolípidos/agonistas , Administración Oral , Animales , Células CHO , Cricetinae , Cricetulus , Clorhidrato de Fingolimod , Humanos , Linfocitos/efectos de los fármacos , Ratones , Estructura Molecular , Naftalenos/administración & dosificación , Naftalenos/farmacología , Propanoles/administración & dosificación , Propanoles/farmacología , Glicoles de Propileno , Esfingosina/análogos & derivados , Relación Estructura-ActividadRESUMEN
Structure-activity relationship of sphingosine-1-phosphate receptor agonist was examined. In terms of reducing the flexibility of molecule, hit compound 1 was modified to improve S1P(1) agonistic activity as well as selectivity over S1P(3) agonistic activity. Novel S1P agonists with cinnamyl scaffold or 1,2,5,6-tetrahydropyridine scaffold were identified.