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1.
ACS Med Chem Lett ; 14(8): 1088-1094, 2023 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-37583812

RESUMO

Glutamate plays a key role in cognition and mood, and it has been shown that inhibiting ionotropic glutamate receptors disrupts cognition, while enhancing ionotropic receptor activity is pro-cognitive. One approach to elevating glutamatergic tone has been to antagonize presynaptic metabotropic glutamate receptor 2 (mGluR2). A desire for selectivity over the largely homologous mGluR3 motivated a strategy to achieve selectivity through the identification of mGluR2 negative allosteric modulators (NAMs). Extensive screening and optimization efforts led to the identification of a novel series of 4-arylquinoline-2-carboxamides. This series was optimized for mGluR2 NAM potency, clean off-target activity, and desirable physical properties, which resulted in the identification of improved C4 and C7 substituents. The initial lead compound from this series was Ames-positive in a single strain with metabolic activation, indicating that a reactive metabolite was likely responsible for the genetic toxicity. Metabolic profiling and Ames assessment across multiple analogs identified key structure-activity relationships associated with Ames positivity. Further optimization led to the Ames-negative mGluR2 negative allosteric modulator MK-8768.

2.
Bioorg Med Chem Lett ; 18(18): 4963-7, 2008 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-18760600

RESUMO

A homology model of the nicotinic acid receptor GPR109A was constructed based on the X-ray crystal structure of bovine rhodopsin. An HTS hit was docked into the homology model. Characterization of the binding pocket by a grid-based surface calculation of the docking model suggested that a larger hydrophobic body plus a polar tail would improve interaction between the ligand and the receptor. The designed compounds were synthesized, and showed significantly improved binding affinity and activation of GPR109A.


Assuntos
Modelos Moleculares , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/farmacologia , Sítios de Ligação , Técnicas de Química Combinatória , Humanos , Estrutura Molecular , Niacina/metabolismo , Agonistas Nicotínicos/química , Receptores Nicotínicos , Relação Estrutura-Atividade , ortoaminobenzoatos/química
4.
Org Lett ; 11(23): 5394-7, 2009 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-19943697

RESUMO

A stereocontrolled synthesis of a complex pentacycle embodying the molecular architecture of the cortistatin class of natural products was achieved from the (+)-Hajos-Parrish ketone. The cornerstone of our approach is a hypervalent iodine induced tandem intramolecular oxidative dearomatization and nitrile oxide cycloaddition. The manner in which these ring formations were orchestrated has yielded a rather concise strategy for synthesis.


Assuntos
Produtos Biológicos/síntese química , Iodo/química , Neuropeptídeos/síntese química , Animais , Produtos Biológicos/química , Ciclização , Estrutura Molecular , Neuropeptídeos/química , Poríferos/química , Estereoisomerismo
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