RESUMEN
Transient receptor potential vanilloid 1 (TRPV1) is a Ca(2+)-permeable non-selective cation channel that transmits pain signals. TRPV1 is activated by multiple stimuli such as capsaicin, acid, and heat. During inflammation, TRPV1 is reported to be sensitized by protein kinase C (PKC) in dorsal root ganglia (DRG) neurons, which leads to reduction in the threshold of the temperature for TRPV1 activation to body temperature. This sensitization is considered to contribute to chronic inflammatory pain. In a previous study, we discovered orally active 5,5-diarylpentadienamide TRPV1 antagonists. To examine the effects of our TRPV1 antagonists on PKC-sensitized TRPV1, we developed an in vitro assay system to monitor the TRPV1 sensitization by PKC. In this assay system, our TRPV1 antagonists, such as (2E,4Z)-N-[(3R)-3-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolyl]-5-(4-isopropoxyphenyl)-5-(4-trifluoromethylphenyl)-2,4-pentadienamide (K-685), inhibited the activation of TRPV1 sensitized by PKC. The potentiation of heat-induced inward currents by PKC was seen in rat DRG neurons, and K-685 attenuated these currents. Furthermore, K-685 reversed the thermal hyperalgesia and mechanical allodynia in a rat complete Freund's adjuvant-induced inflammatory pain model. These results therefore suggest that K-685 has a strong potential as a new analgesic drug for the treatment of inflammatory pain.
Asunto(s)
Analgésicos , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/genética , Adyuvante de Freund/efectos adversos , Inflamación/complicaciones , Ácidos Pentanoicos/farmacología , Ácidos Pentanoicos/uso terapéutico , Proteína Quinasa C/fisiología , Quinolonas/farmacología , Quinolonas/uso terapéutico , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/metabolismo , Animales , Dolor Crónico/etiología , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
We have developed a novel and potent chemical series of 5,5-diphenylpentadienamides for targeting TRPV1 in vitro and in vivo. In this investigation, we examined a variety of replacements for the 5-position of dienamides with the goal of addressing issues related to pharmacokinetics. Our data suggest that substitution with alkoxy groups on the phenyl ring at the 5-position increases their ability to penetrate the blood-brain barrier. This investigation culminated in the discovery of compound (R)-36b, which showed a good pharmacokinetic profile. In vivo, compound (R)-36b was found to be effective at reversing mechanical allodynia in rats in a dose-dependent manner, and it reversed thermal hyperalgesia in a model of neuropathic pain induced by sciatic nerve injury.
Asunto(s)
Alcadienos/síntesis química , Amidas/síntesis química , Analgésicos/síntesis química , Quinolonas/síntesis química , Canales Catiónicos TRPV/antagonistas & inhibidores , Alcadienos/farmacocinética , Alcadienos/farmacología , Amidas/farmacocinética , Amidas/farmacología , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Barrera Hematoencefálica/metabolismo , Calcio/metabolismo , Capsaicina/farmacología , Perros , Antígenos Nucleares del Virus de Epstein-Barr/genética , Células HEK293 , Haplorrinos , Humanos , Hiperalgesia/prevención & control , Masculino , Microsomas Hepáticos/metabolismo , Neuralgia/prevención & control , Quinolonas/farmacocinética , Quinolonas/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Canales Catiónicos TRPV/agonistas , Canales Catiónicos TRPV/genéticaRESUMEN
Based on the previously reported lead compound, a series of benzofuran derivatives were prepared to study their antagonistic activities to A(2A) receptor. The replacement of the phenyl group at the 4-position with a heterocyclic ring improved the PK profile and aqueous solubility. From these studies, we discovered a potent new A(2A) antagonist, 12a, which has both a good oral bioavailability and in vivo efficacy on motor disability in MPTP-treated common marmosets.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Benzofuranos/síntesis química , Benzofuranos/farmacología , Animales , Benzofuranos/química , Disponibilidad Biológica , Callithrix , Trastornos de la Destreza Motora/tratamiento farmacológico , Solubilidad , Relación Estructura-ActividadRESUMEN
A series of benzofuran derivatives were prepared to study their antagonistic activities to the A(2A) receptor. Replacement of the ester group of the lead compound 1 with phenyl ring improved the PK profile, while modifications of the amide moiety showed enhanced antagonistic activity. From these studies, compounds 13c, 13f, and 24a showed good potency in vitro and were identified as novel A(2A) receptor antagonists suitable for oral activity evaluation in animal models of catalepsy.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Benzofuranos/síntesis química , Benzofuranos/metabolismo , Receptor de Adenosina A2A/metabolismo , Animales , Benzofuranos/farmacología , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Unión Proteica/fisiología , Ratas , Relación Estructura-ActividadRESUMEN
To improve the poor pharmacokinetic characteristics of VLA-4 inhibitors, novel piperazinylphenylalanine derivatives were designed. This structure is expected to improve physicochemical properties by increasing overall basicity. By changing components at the 4-position of piperazine and the terminal group of the amido bond, 12t was found to be the most potent of this series of compounds. In addition, dichlorobenzoyl derivative 12aa exhibited better oral availability and showed efficacy in an in vivo model after oral administration.