RESUMO
We describe here our attempts to optimise the human fatty acid amide hydrolase (FAAH) inhibition and physicochemical properties of our previously reported tetrasubstituted azetidine urea FAAH inhibitor, VER-156084. We describe the SAR of a series of analogues and conclude with the demonstration of in vivo dose-dependant FAAH inhibition in an anandamide-loading study in rats.
Assuntos
Amidoidrolases/antagonistas & inibidores , Azetidinas/farmacologia , Inibidores Enzimáticos/farmacologia , Ureia/farmacologia , Amidoidrolases/metabolismo , Animais , Azetidinas/síntese química , Azetidinas/química , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Canal de Potássio ERG1 , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Modelos Moleculares , Estrutura Molecular , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/químicaRESUMO
Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray structures combined with molecular modeling led to the rational displacement of a conserved water molecule leading to enhanced affinity for Hsp90 as measured by fluorescence polarization, isothermal titration calorimetry and surface plasmon resonance assays. This displacement was achieved with a nitrile group, presenting an example of efficient gain in binding affinity with minimal increase in molecular weight. Some compounds in this chemical series inhibit the proliferation of human cancer cell lines in vitro and cause depletion of oncogenic Hsp90 client proteins and concomitant elevation of the co-chaperone Hsp70. In addition, one compound was demonstrated to be orally bioavailable in the mouse. This work demonstrates the power of structure-based design for the rapid evolution of potent Hsp90 inhibitors and the importance of considering conserved water molecules in drug design.
Assuntos
Desenho de Fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Pirimidinas/química , Pirróis/química , Água/química , Administração Oral , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células HCT116 , Proteínas de Choque Térmico HSP90/metabolismo , Meia-Vida , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirróis/síntese química , Pirróis/farmacocinética , Relação Estrutura-AtividadeRESUMO
We report the discovery of a novel, chiral azetidine urea inhibitor of Fatty Acid Amide Hydrolase (FAAH,) and describe the surprising species selectivity of VER-156084 versus rat and human FAAH and also hCB1.
Assuntos
Amidoidrolases/antagonistas & inibidores , Amidoidrolases/química , Azetidinas/química , Azetidinas/síntese química , Inibidores Enzimáticos/síntese química , Piperidinas/síntese química , Ureia/química , Animais , Azetidinas/farmacologia , Catálise , Química Farmacêutica/métodos , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Camundongos Knockout , Modelos Químicos , Piperidinas/farmacologia , Ratos , Receptor CB1 de Canabinoide/química , EstereoisomerismoRESUMO
We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine.
Assuntos
Catepsinas/antagonistas & inibidores , Química Farmacêutica/métodos , Inibidores de Cisteína Proteinase/síntese química , Nitrilas/síntese química , Peptídeos/química , Pirimidinas/química , Pirimidinas/síntese química , Animais , Inibidores de Cisteína Proteinase/farmacologia , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Masculino , Conformação Molecular , Nitrilas/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.
Assuntos
Catepsinas/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Pirimidinas/síntese química , Pirimidinas/farmacologia , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Catepsina L , Técnicas de Química Combinatória , Cisteína Endopeptidases , Humanos , Masculino , Estrutura Molecular , Esclerose Múltipla/tratamento farmacológico , Dor/tratamento farmacológico , Pirimidinas/sangue , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Selective activation of peripheral cannabinoid CB1 receptors has the potential to become a valuable therapy for chronic pain conditions as long as central nervous system effects are attenuated. A new class of cannabinoid ligands was rationally designed from known aminoalkylindole agonists and showed good binding and functional activities at human CB1 and CB2 receptors. This has led to the discovery of a novel CB1/CB2 dual agonist, naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (13), which displays good oral bioavailability, potent antihyperalgesic activity in animal models, and limited brain penetration.
Assuntos
Analgésicos/síntese química , Encéfalo/metabolismo , Hiperalgesia/tratamento farmacológico , Naftalenos/síntese química , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas , Administração Oral , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Disponibilidade Biológica , Cricetinae , Cricetulus , AMP Cíclico/biossíntese , Humanos , Técnicas In Vitro , Microssomos Hepáticos/metabolismo , Naftalenos/farmacocinética , Naftalenos/farmacologia , Ensaio Radioligante , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
Vanilloid receptor 1 (VR1, TRPV1) is a cation-selective ion channel that is expressed on primary afferent neurons and is upregulated following inflammation and nerve damage. Blockers of this channel may have utility in the treatment of chronic nociceptive and neuropathic pain. Here, we describe the optimization from a high throughput screening hit, of a series of 6-aryl-7-isopropylquinazolinones that are TRPV1 antagonists in vitro. We also demonstrate that one compound is active in vivo against capsaicin-induced hyperalgesia and in models of neuropathic and nociceptive pain in the rat.