RESUMEN
Pyridylmethylsulfonamide series were the first reported example of positive allosteric modulators (PAM) of the mGlu2 receptor. The hydroxyacetophenone scaffold is a second series of mGlu2 PAMs we have identified. This series of molecules are potent mGlu2 potentiators and possess significant CysLT1 (cysteinyl leukotriene receptor 1) antagonist activity, showing in vivo efficacy in a dural plasma protein extravasation (PPE) model of migraine. In this paper, we describe the dual SAR, pharmacokinetics and preclinical in vivo efficacy data for a tetrazole containing hydroxyacetophenone scaffold.
Asunto(s)
Descubrimiento de Drogas , Trastornos Migrañosos/tratamiento farmacológico , Receptores de Leucotrienos/metabolismo , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Sulfonamidas/farmacología , Regulación Alostérica/efectos de los fármacos , Animales , Perros , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Ratas , Receptores de Glutamato Metabotrópico/agonistas , Relación Estructura-Actividad , Sulfonamidas/administración & dosificación , Sulfonamidas/químicaRESUMEN
Calcitonin gene-related peptide (CGRP), a potent dilator of cerebral and dural vasculature, is known to be elevated in plasma and cerebral spinal fluid during migraine attacks. Selective blockade of the CGRP receptor offers the promise of controlling migraine headache more effectively and without the side-effects associated with the use of triptans. Our efforts to develop a novel, peptide-based CGRP antagonist focused on the C-terminal portion of the peptide which is known to bind the receptor but lack agonist properties. Extensive SAR studies of the C-terminal CGRP (27-37) region identified a novel cyclic structure: Bz-Val-Tyr-cyclo[Cys-Thr-Asp-Val-Gly-Pro-Phe-Cys]-Phe-NH(2) (23) with a kb value of 0.126 nM against the cloned human CGRP receptor. Additional SAR studies directed at enhancement of potency and improvement of physicochemical properties yielded a series of analogs with kb values in the 0.05-0.10 nM range.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Péptidos/química , Péptidos/farmacología , HumanosRESUMEN
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.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Ésteres/síntesis química , Antagonistas de Aminoácidos Excitadores/síntesis química , Isoquinolinas/síntesis química , Trastornos Migrañosos/tratamiento farmacológico , Profármacos/síntesis química , Receptores de Ácido Kaínico/antagonistas & inhibidores , Enfermedad Aguda , Administración Oral , Animales , Disponibilidad Biológica , Calcio/metabolismo , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Línea Celular , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ésteres/química , Ésteres/farmacología , Antagonistas de Aminoácidos Excitadores/química , Antagonistas de Aminoácidos Excitadores/farmacología , Humanos , Isoquinolinas/química , Isoquinolinas/farmacología , Profármacos/química , Profármacos/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas WistarAsunto(s)
Sistemas de Transporte de Aminoácidos Neutros/antagonistas & inhibidores , Química Encefálica/efectos de los fármacos , Glicina/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Proteínas de Transporte de Glicina en la Membrana Plasmática , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Sarcosina/análogos & derivados , Sarcosina/farmacologíaRESUMEN
The excitatory neurotransmitter glutamate has been implicated in both migraine and persistent pain. The identification of the kainate receptor GLU(K5) in dorsal root ganglia, the dorsal horn, and trigeminal ganglia makes it a target of interest for these indications. We examined the in vitro and in vivo pharmacology of the competitive GLU(K5)-selective kainate receptor antagonist LY466195 [(3S,4aR,6S,8aR)-6-[[(2S)-2-carboxy-4,4-difluoro-1-pyrrolidinyl]-methyl]decahydro-3-isoquinolinecarboxylic acid)], the most potent GLU(K5) antagonist described to date. Comparisons were made to the competitive GLU(K5)/alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]-decahydroisoquinoline-3-carboxylic acid], other decahydroisoquinoline GLU(K5) receptor antagonists, and the noncompetitive AMPA receptor antagonist LY300168 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodi-azepine]. When characterized electrophysiologically in rat dorsal root ganglion neurons, LY466195 antagonized kainate (30 microM)-induced currents with an IC50 value of 0.045 +/- 0.011 microM. In HEK293 cells transfected with GLU(K5), GLU(K2)/GLU(K5), or GLU(K5)/GLU(K6) receptors, LY466195 produced IC50 values of 0.08 +/- 0.02, 0.34 +/- 0.17, and 0.07 +/- 0.02 microM, respectively. LY466195 was efficacious in a dural plasma protein extravasation (PPE) model of migraine with an ID100 value of 100 microg/kg i.v. LY466195 was also efficacious in the c-fos migraine model, with a dose of 1 microg/kg i.v. significantly reducing the number of Fos-positive cells in the rat nucleus caudalis after electrical stimulation of the trigeminal ganglion. Furthermore, LY466195 showed no contractile activity in the rabbit saphenous vein in vitro. The diethyl ester prodrug of LY466195 was also efficacious in the same PPE and c-fos models after oral administration at doses of 10 and 100 microg/kg, respectively while having no N-methyl-D-aspartate antagonist-like behavioral effects at oral doses up to 100 mg/kg.