RESUMO
The metabotropic glutamate receptor 4 (mGluR4) is an emerging target for the treatment of Parkinson's disease (PD). However, since the discovery of its therapeutic potential, no ligand has been successfully developed enough to be tested in the clinic. In the present paper, we report for the first time the medicinal chemistry efforts conducted around the pharmacological tool (-)-PHCCC. This work led to the identification of compound 40, a potent and selective mGluR4 positive allosteric modulator (PAM) with good water solubility and demonstrating consistent activity across validated preclinical rodent models of PD motor symptoms after intraperitoneal administration: haloperidol-induced catalepsy in mouse and the rat 6-hydroxydopamine (6-OHDA) lesion model. Moreover, we also describe the identification of compound 60 a close analogue of compound 40 with improved pharmacokinetic profile after oral administration. On the basis of its favorable and unique preclinical profile, compound 60 (PXT002331, now foliglurax) was nominated as a candidate for clinical development.
Assuntos
Antiparkinsonianos/farmacologia , Encéfalo/efeitos dos fármacos , Descoberta de Drogas , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Regulação Alostérica , Animais , Antiparkinsonianos/farmacocinética , Cromatografia Líquida , Células HEK293 , Humanos , Espectrometria de Massas , Camundongos , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Relação Estrutura-AtividadeRESUMO
Unique chemical methodology enables the synthesis of innovative and diverse scaffolds and chemotypes and allows access to previously unexplored "chemical space." Compound collections based on such new synthetic methods can provide small-molecule probes of proteins and/or pathways whose functions are not fully understood. We describe the identification, characterization, and evolution of two such probes. In one example, a pathway-based screen for DNA damage checkpoint inhibitors identified a compound, MARPIN (ATM and ATR pathway inhibitor) that sensitizes p53-deficient cells to DNA-damaging agents. Modification of the small molecule and generation of an immobilized probe were used to selectively bind putative protein target(s) responsible for the observed activity. The second example describes a focused library approach that relied on tandem multicomponent reaction methodologies to afford a series of modulators of the heat shock protein 70 (Hsp70) molecular chaperone. The synthesis of libraries based on the structure of MAL3-101 generated a collection of chemotypes, each modulating Hsp70 function, but exhibiting divergent pharmacological activities. For example, probes that compromise the replication of a disease-associated polyomavirus were identified. These projects highlight the importance of chemical methodology development as a source of small-molecule probes and as a drug discovery starting point.
Assuntos
Desenho de Fármacos , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Sondas Moleculares , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Proteínas de Ligação a DNA/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Sondas Moleculares/síntese química , Sondas Moleculares/química , Sondas Moleculares/farmacologia , Polyomavirus/fisiologia , Infecções por Polyomavirus/tratamento farmacológico , Infecções por Polyomavirus/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Supressoras de Tumor/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
After nitrogen, fluorine is probably the next most favorite hetero-atom for incorporation into small molecules in life science-oriented research. This review focuses on a particular fluorinated substituent, the trifluoromethoxy group, which is finding increased utility as a substituent in bioactives, but it is still perhaps the least well understood fluorine substituent in currency. The present review will give an overview of the synthesis, properties and reactivity of this important substituent.