RESUMO
One of the most commonly used strategies to reduce hERG (human ether-a-go-go) activity in the drug candidates is introduction of a carboxylic acid group. During the optimization of PPARδ modulators, some of the compounds containing a carboxylic acid were found to inhibit the hERG channel in a patch clamp assay. By modifying the basicity of the imidazole core, potent and selective PPARδ modulators that do not inhibit hERG channel were identified. Some of the modulators have excellent pharmacokinetic profiles in mice.
Assuntos
Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , PPAR delta/química , Bloqueadores dos Canais de Potássio/química , Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/metabolismo , Meia-Vida , Humanos , Cinética , PPAR delta/genética , PPAR delta/metabolismo , Bloqueadores dos Canais de Potássio/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Relação Estrutura-Atividade , Ativação Transcricional/efeitos dos fármacosRESUMO
[This corrects the article DOI: 10.1021/acsmedchemlett.8b00287.].
RESUMO
The X-ray structure of the previously reported PPARδ modulator 1 bound to the ligand binding domain (LBD) revealed that the amide moiety in 1 exists in the thermodynamically disfavored cis-amide orientation. Isosteric replacement of the cis-amide with five-membered heterocycles led to the identification of imidazole 17 (MA-0204), a potent, selective PPARδ modulator with good pharmacokinetic properties. MA-0204 was tested in vivo in mice and in vitro in patient-derived muscle myoblasts (from Duchenne Muscular Dystrophy (DMD) patients); 17 altered the expression of PPARδ target genes and improved fatty acid oxidation, which supports the therapeutic hypothesis for the study of MA-0204 in DMD patients.
RESUMO
Compound 1 regulates significantly fewer genes than the PPARδ modulator, GW501516. Both compounds are efficacious in a thermal injury model of muscle regeneration. The restricted gene profile of 1 relative to GW501516 suggests that 1 may be pharmacoequivalent to GW501516 with fewer PPAR-related safety concerns.
Assuntos
PPAR delta/metabolismo , Tiazóis/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
Optimization of benzamide PPARδ modulator 1 led to (E)-6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy)-4-methylhex-4-enoic acid (18), a potent selective PPARδ modulator with significantly improved exposure in multiple species following oral administration.
Assuntos
Benzamidas/farmacocinética , Administração Oral , Animais , Benzamidas/administração & dosagem , Benzamidas/sangue , Relação Dose-Resposta a Droga , Humanos , Injeções Intravenosas , Macaca fascicularis , Masculino , Camundongos , Estrutura Molecular , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
A new facile approach toward natural and unnatural indanones has been developed, featuring a solid-supported [2+2+2] cyclotrimerization as the key step. This strategy has been applied to the chemo- and regioselective assembly of indanone arrays and to the total synthesis of a recently isolated indanone marine natural product.
RESUMO
The transition-metal-catalyzed [2+2+2] cyclotrimerization of a diyne and an alkyne provides a convergent route to highly-substituted aromatic rings. This reaction possesses distinct drawbacks, especially low chemo- and regioselectivities, which hamper its application in combinatorial synthesis. These problems have been solved by the development of solid-supported [2+2+2]-cycloaddition reactions. If conducted on a solid-support, this reaction enables rapid combinatorial access to diverse sets of carbo- and heterocyclic small-molecule arrays. The scope of this methodology has been investigated by examining different immobilization strategies, different diyne precursors, and a variety of functionalized alkyne reaction partners. Overall, isoindoline, phthalan, and indan libraries were assembled in good to excellent yields and with high purities.
RESUMO
The formation of pyridines via a crossed [2 + 2 + 2] cycloaddition has been achieved on a solid-support for the first time.
RESUMO
A new family of ring-annulated inositols with "locked" conformations has been designed to deliver a range of these biologically important entities in "unnatural conformations" while retaining their "natural configurations". The simple "tool" of trans ring fusion has been used to "lock" the conformation of the annulated inositols. Short, simple syntheses of a range of these novel cyclitols have been achieved from readily available aromatic precursors such as tetralin and indane. Along the way, annulated C(2)-symmetric cyclohexadiene-trans-diol (trans-CHD) derivatives have been prepared for the first time and serve as the pivotal building blocks for generating the oxy-functionalization pattern of inositols. The presence of chemo-differentiated hydroxyl groups in our novel inositols is expected to facilitate the installation of phosphate diversity to harness the biological potential of these entities.