RESUMO
A series of triaryl pyrazoles were identified as potent pan antagonists for the retinoic acid receptors (RARs) α, ß and γ. X-ray crystallography and structure-based drug design were used to improve selectivity for RARγ by targeting residue differences in the ligand binding pockets of these receptors. This resulted in the discovery of novel antagonists which maintained RARγ potency but were greater than 500-fold selective versus RARα and RARß. The potent and selective RARγ antagonist LY2955303 demonstrated good pharmacokinetic properties and was efficacious in the MIA model of osteoarthritis-like joint pain. This compound demonstrated an improved margin to RARα-mediated adverse effects.
Assuntos
Desenho de Fármacos , Osteoartrite/tratamento farmacológico , Dor/tratamento farmacológico , Piperazinas/farmacologia , Pirazóis/farmacologia , Receptores do Ácido Retinoico/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Receptor gama de Ácido RetinoicoRESUMO
We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models.
Assuntos
Isoquinolinas/farmacologia , Dor/tratamento farmacológico , Pró-Fármacos/farmacologia , Receptores de Ácido Caínico/antagonistas & inibidores , Tetrazóis/farmacologia , Administração Oral , Sequência de Aminoácidos , Animais , Modelos Animais de Doenças , Isoquinolinas/química , Masculino , Dados de Sequência Molecular , Pró-Fármacos/química , Ratos , Ratos Sprague-Dawley , Receptores de Ácido Caínico/química , Relação Estrutura-Atividade , Tetrazóis/químicaRESUMO
The synthesis and structure-activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.
Assuntos
Isoquinolinas/farmacologia , Dor/tratamento farmacológico , Pró-Fármacos/farmacologia , Receptores de Ácido Caínico/antagonistas & inibidores , Administração Oral , Sequência de Aminoácidos , Animais , Modelos Animais de Doenças , Haplorrinos , Isoquinolinas/química , Dados de Sequência Molecular , Pró-Fármacos/química , Receptores de Ácido Caínico/química , Relação Estrutura-AtividadeRESUMO
In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC50 = 2 nM), PK properties, and a robust PK/PD relationship.
RESUMO
Amino acids 5 and 7, two potent and selective competitive GluR5 KA receptor antagonists, exhibited high GluR5 receptor affinity over other glutamate receptors. Their ester prodrugs 6 and 8 were orally active in three models of pain: reversal of formalin-induced paw licking, carrageenan-induced thermal hyperalgesia, and capsaicin-induced mechanical hyperalgesia.
Assuntos
Aminoácidos/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Dor/tratamento farmacológico , Receptores de Ácido Caínico/antagonistas & inibidores , Analgésicos/farmacocinética , Animais , Disponibilidade Biológica , Linhagem Celular , Modelos Animais de Doenças , Humanos , Hiperalgesia/tratamento farmacológico , Ratos , Receptores de AMPA/metabolismo , Proteínas Recombinantes/metabolismo , Medula Espinal/fisiopatologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismoRESUMO
Amino diacid 3, a highly selective competitive GluR5 kainate receptor antagonist, exhibited high GluR5 receptor affinity and selectivity over other glutamate receptors. Its diethyl ester prodrug 4 was orally active in two models of migraine: the neurogenic dural plasma protein extravasation model and the nucleus caudalis c-fos expression model. These data suggest that a GluR5 kainate receptor antagonist might be an efficacious antimigraine therapy with a novel mechanism of action.
Assuntos
Ácidos Carboxílicos/síntese química , Ésteres/síntese química , Antagonistas de Aminoácidos Excitatórios/síntese química , Isoquinolinas/síntese química , Transtornos de Enxaqueca/tratamento farmacológico , Pró-Fármacos/síntese química , Receptores de Ácido Caínico/antagonistas & inibidores , Doença Aguda , Administração Oral , Animais , Disponibilidade Biológica , Cálcio/metabolismo , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Linhagem Celular , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ésteres/química , Ésteres/farmacologia , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Ensaio Radioligante , Ratos , Ratos WistarRESUMO
We report the synthesis and characterization of novel 3-aryl indoles as potent and efficacious progesterone receptor (PR) antagonists with potential for the treatment of uterine fibroids. These compounds demonstrated excellent selectivity over other steroid nuclear hormone receptors such as the mineralocorticoid receptor (MR). They were prepared from 2-bromo-6-nitro indole in four to six steps using a Suzuki cross-coupling as the key step. Compound 8f was orally active in the complement 3 model of progesterone antagonism in the rat uterus and demonstrated partial antagonism in the McPhail model of progesterone activity.
RESUMO
The major excitatory neurotransmitter in the central nervous system, (S)-glutamic acid , activates both ionotropic and metabotropic excitatory amino acid receptors. Its importance in connection to neurological and psychiatric disorders has directed great attention to the development of compounds that modulate the effects of this endogenous ligand. Whereas L-carboxycyclopropylglycine (L-CCG-1) is a potent agonist at, primarily, group II metabotropic glutamate receptors, alkylation of at the alpha-carbon notoriously result in group II mGluR antagonists, of which the most potent compound described so far, LY341495, displays IC(50) values of 23 and 10 nM at the group II receptor subtypes mGlu2 and mGlu3, respectively. In this study we synthesized a series of structural analogues of in which the xanthyl moiety is replaced by two substituted-phenyl groups. The pharmacological characterization shows that these novel compounds have very high affinity for group II mGluRs when tested as their racemates. The most potent analogues demonstrate K(i) values in the range of 5-12 nM, being thus comparable to LY341495.