RESUMO
A series of 4-(3-biaryl)quinolines with sulfone substituents on the terminal aryl ring (8) was prepared as potential LXR agonists. High affinity LXRbeta ligands with generally modest binding selectivity over LXRalpha and excellent agonist potency in LXR functional assays were identified. Many compounds had LXRbeta binding IC(50) values <10 nM while the most potent had EC(50) values <1.0 nM in an ABCA1 mRNA induction assay in J774 mouse cells with efficacy comparable to T0901317. Sulfone 8a was further evaluated in LDL (-/-) mice and shown to reduce atherosclerotic lesion progression.
Assuntos
Receptores Nucleares Órfãos/agonistas , Quinolinas/química , Sulfonas/química , Animais , Aterosclerose/tratamento farmacológico , Sítios de Ligação , Linhagem Celular , Simulação por Computador , Humanos , Lipoproteínas LDL/deficiência , Lipoproteínas LDL/genética , Lipoproteínas LDL/metabolismo , Receptores X do Fígado , Camundongos , Camundongos Knockout , Microssomos/metabolismo , Receptores Nucleares Órfãos/metabolismo , Ratos , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/uso terapêuticoRESUMO
A series of 4-(3-aryloxyaryl)quinolines with sulfone substituents on the terminal aryl ring (7) was prepared as LXR agonists. High affinity LXR ligands with excellent agonist potency and efficacy in functional assays of LXR activity were identified. In general, these sulfone agonists were equal to or superior to previously described alcohol and amide analogs in terms of affinity, functional potency, and microsomal stability. Many of the sulfones had LXRbeta binding IC(50) values <10nM while the most potent compounds in an ABCA1 mRNA induction assay in J774 mouse cells had EC(50) values <10nM and were as efficacious as T0901317.
Assuntos
Receptores Nucleares Órfãos/agonistas , Quinolinas/química , Sulfonas/química , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Sítios de Ligação , Linhagem Celular , Simulação por Computador , Humanos , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacologia , Ligação de Hidrogênio , Receptores X do Fígado , Camundongos , Microssomos Hepáticos/metabolismo , Receptores Nucleares Órfãos/metabolismo , Quinolinas/síntese química , Quinolinas/farmacologia , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonas/síntese química , Sulfonas/farmacologiaRESUMO
An efficient and mild method to couple aryl bromides and activated non-allylic alcohols in a Heck reaction with tandem isomerization to selectively afford high yields of 1,5-diarylalkan-1-ones has been developed. Mechanistic insight was gained through NMR studies of products derived from deuterium-labeled intermediates.
Assuntos
Álcoois Benzílicos/química , Brometos/química , Paládio/química , Catálise , Espectroscopia de Ressonância Magnética , Estrutura Molecular , EstereoisomerismoRESUMO
During the last thirty years, concern over stereoselectivity of drug action has drawn a great deal of interest within the pharmaceutical field due to an improved understanding of the pharmacology and pharmacokinetics of enantiomers. Developing single enantiomers versus racemates or introducing a single enantiomer following the development of the racemic mixture appears to be the new trend. The intellectual property status of single enantiomers from racemates may be unclear. Drug discoverers and patent attorneys must examine the examples of the past to establish an appropriate pathway towards the development and intellectual property protection of chiral drugs. The review will focus on the patenting of an enantiomer in view of the prior art disclosure for the racemic mixture.
Assuntos
Indústria Farmacêutica/legislação & jurisprudência , Patentes como Assunto/legislação & jurisprudência , Preparações Farmacêuticas/química , Desenho de Fármacos , Propriedade Intelectual , Preparações Farmacêuticas/síntese química , Estereoisomerismo , Estados UnidosRESUMO
The design, synthesis, and biological evaluation of the 2-phenyl-isoindole-1,3-diones will be discussed. Detailed modeling studies with X-ray support were used to understand the ligand binding orientation and observed selectivity.
Assuntos
Receptor beta de Estrogênio/agonistas , Indóis/química , Ftalimidas/química , Cristalografia por Raios X , Receptor beta de Estrogênio/química , Humanos , Indóis/síntese química , Ligantes , Ftalimidas/síntese químicaRESUMO
A new series of 3,3-disubstituted-5-aryloxindoles has been synthesized and evaluated for progesterone receptor antagonist (PR) activity in a T47D cell alkaline phosphatase assay and for their ability to bind PR in competition binding studies. In this communication, the synthesis and structure-activity relationships (SARs) of various 3,3-substituents are discussed where it is clear that small alkyl and spiroalkyl groups are required to achieve better PR antagonist activity.
