RESUMO
Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase that degrades the fatty acid amide family of signaling lipids, including the endocannabinoid anandamide. Genetic or pharmacological inactivation of FAAH leads to analgesic and anti-inflammatory phenotypes in rodents without showing the undesirable side effects observed with direct cannabinoid receptor agonists, indicating that FAAH may represent an attractive therapeutic target for the treatment of inflammatory pain and other nervous system disorders. Herein, we report the discovery and characterization of a highly efficacious and selective FAAH inhibitor PF-04457845 (23). Compound 23 inhibits FAAH by a covalent, irreversible mechanism involving carbamylation of the active-site serine nucleophile of FAAH with high in vitro potency (k(inact)/K(i) and IC(50) values of 40300 M(-1) s(-1) and 7.2 nM, respectively, for human FAAH). Compound 23 has exquisite selectivity for FAAH relative to other members of the serine hydrolase superfamily as demonstrated by competitive activity-based protein profiling. Oral administration of 23 at 0.1 mg/kg results in efficacy comparable to that of naproxen at 10 mg/kg in a rat model of inflammatory pain. Compound 23 is being evaluated in human clinical trials.
RESUMO
The inhibition of the cytosolic isoenzyme BCAT that is expressed specifically in neuronal tissue is likely to be useful for the treatment of neurodegenerative and other neurological disorders where glutamatergic mechanisms are implicated. Compound 2 exhibited an IC50 of 0.8 microM in the hBCATc assays; it is an active and selective inhibitor. Inhibitor 2 also blocked calcium influx into neuronal cells following inhibition of glutamate uptake, and demonstrated neuroprotective efficacy in vivo. SAR, pharmacology, and the crystal structure of hBCATc with inhibitor 2 are described.
Assuntos
Benzofuranos/síntese química , Benzofuranos/uso terapêutico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Sulfonamidas/síntese química , Sulfonamidas/uso terapêutico , Transaminases/antagonistas & inibidores , Animais , Benzofuranos/química , Cálcio/antagonistas & inibidores , Cálcio/metabolismo , Células Cultivadas , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Ácido Glutâmico/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Humanos , Técnicas In Vitro , Modelos Moleculares , Estrutura Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Endogâmicos Lew , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
A benzylpiperidine analogue with an acetylenic linker, 5-(3-[4-(4-fluorobenzyl)-piperidin-1-yl]-prop-1-ynyl)-1,3-dihydrobenzimidazol-2-one (3), was identified as a chemical lead with excellent activity at the NR1A/2B receptor (IC50=3 nM). Efforts to optimize this activity led to focused modifications around the structural motif of 3. The synthesis and SAR studies are discussed.
