RESUMEN
Novel, low brain penetrant, orally bioavailable CB1 receptor agonists were designed starting from a mature lead series of potent brain penetrant CB1 receptor agonists. Increasing the calculated polar surface area was found to be a good strategy for reducing brain penetration whilst retaining drug-like properties. This in silico approach led to the discovery of LBP1, an orally bioavailable, low brain penetrant CB1 receptor agonist with robust activity in rodent models of neuropathic pain and a good preclinical therapeutic profile, which was selected for clinical development.
Asunto(s)
Diseño de Fármacos , Indoles/síntesis química , Neuralgia/tratamiento farmacológico , Oxadiazoles/síntesis química , Receptor Cannabinoide CB1/agonistas , Animales , Encéfalo/irrigación sanguínea , Encéfalo/metabolismo , Células CACO-2 , Humanos , Indoles/química , Indoles/farmacocinética , Ratones , Oxadiazoles/química , Oxadiazoles/farmacocinética , RatasRESUMEN
Here, we report the identification and optimization of 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives as a novel chemotype with selective cannabinoid CB2 receptor agonist activity. 1 is a potent and selective cannabinoid CB2 receptor agonist (hCB2 pEC(50) = 8.6). The compound was found to be metabolically unstable, which resulted in low oral bioavailability in rat (F(po) = 4%) and possessed off-target activity at the hERG ion channel (pK(i) = 5.5). Systematic modification of physicochemical properties, such as lipophilicity and basicity, was used to optimize the pharmacokinetic profile and hERG affinity of this novel class of cannabinoid CB2 receptor agonists. This led to the identification of 44 as a potent, selective, and orally bioavailable cannabinoid CB2 receptor agonist (hCB2 pEC(50) = 8.0; hERG pK(i) < 4; F(po) = 100%), which was active in a rat spinal nerve ligation model of neuropathic pain.
Asunto(s)
Analgésicos/síntesis química , Óxidos S-Cíclicos/síntesis química , Hidantoínas/síntesis química , Receptor Cannabinoide CB2/agonistas , Administración Oral , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Células CHO , Células CACO-2 , Permeabilidad de la Membrana Celular , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Óxidos S-Cíclicos/farmacocinética , Óxidos S-Cíclicos/farmacología , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , Células HEK293 , Humanos , Hidantoínas/farmacocinética , Hidantoínas/farmacología , Técnicas In Vitro , Masculino , Microsomas Hepáticos/metabolismo , Neuralgia/tratamiento farmacológico , Neuralgia/etiología , Ratas , Ratas Wistar , Nervios Espinales/lesiones , Relación Estructura-ActividadRESUMEN
We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development.
Asunto(s)
Compuestos Heterocíclicos/química , Indoles/química , Receptor Cannabinoide CB1/agonistas , Tiazoles/química , Animales , Sistema Enzimático del Citocromo P-450/metabolismo , Perros , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacocinética , Ratones , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/metabolismo , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacocinéticaRESUMEN
Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia.
Asunto(s)
Compuestos Heterocíclicos/farmacocinética , Receptor Cannabinoide CB1/agonistas , Administración Oral , Animales , Disponibilidad Biológica , Descubrimiento de Drogas , Compuestos Heterocíclicos/administración & dosificación , RatasRESUMEN
Novel indole-3-heterocycles were designed and synthesized and found to be potent CB1 receptor agonists. Starting from a microsomally unstable lead 1, a bioisostere approach replacing a piperazine amide was undertaken. This was found to be a good strategy for improving stability both in vitro and in vivo. This led to the discovery of 24, which had an increased duration of action in the mouse tail flick test in comparison to the lead 1.
Asunto(s)
Compuestos Heterocíclicos/química , Indoles/química , Receptor Cannabinoide CB1/agonistas , Tiadiazoles/química , Animales , Diseño de Fármacos , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacocinética , Indoles/síntesis química , Indoles/farmacocinética , Ratones , Microsomas/metabolismo , Modelos Moleculares , Receptor Cannabinoide CB1/metabolismo , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Tiadiazoles/farmacocinéticaRESUMEN
Bicyclic piperazine derivatives were synthesized as conformationally constrained analogs of N-alkyl piperazines and were found to be potent CB1 receptor agonists. The CB1 receptor agonist activity was dependent upon the absolute configuration of the chiral center of the bicyclic ring system. Although the conformational constraint did not protect the compounds from metabolism by N-dealkylation, several bicyclic analogs were found to be more potent than the unconstrained lead compound. Compound 8b demonstrated potent antinociceptive activity in vivo.
Asunto(s)
Amidas/química , Compuestos de Azabiciclo/síntesis química , Compuestos Bicíclicos con Puentes/química , Indoles/síntesis química , Piperazinas/química , Receptor Cannabinoide CB1/agonistas , Animales , Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/farmacología , Diseño de Fármacos , Humanos , Indoles/química , Indoles/farmacología , Ratones , Microsomas Hepáticos/metabolismo , Piperazinas/síntesis química , Piperazinas/farmacología , Receptor Cannabinoide CB1/metabolismo , Relación Estructura-ActividadRESUMEN
Novel tricyclic indole-3-carboxamides were synthesized as structurally restricted analogs of bicyclic indoles, and found to be potent CB1 cannabinoid receptor agonists. The CB1 agonist activity depended on the absolute configuration of the chiral center of the tricyclic ring. The preferred enantiomer was more potent than the structurally unconstrained lead compound. Structure-activity relationships in the amide side chain of the indole C-3 position were also investigated.
Asunto(s)
Amidas/química , Indoles/química , Receptor Cannabinoide CB1/agonistas , Amidas/síntesis química , Amidas/farmacocinética , Animales , Diseño de Fármacos , Humanos , Ratones , Microsomas/metabolismo , Receptor Cannabinoide CB1/metabolismo , Relación Estructura-ActividadRESUMEN
Presently, there are numerous structural classes of cannabinoid receptor agonists, all of which require solubilization for experimental purposes. One strategy for solubilizing water-insoluble tetrahydrocannabinols is conversion of the phenolic hydroxyl to a morpholinobutyryloxy substituent. The hydrochloride salts of these analogs are water-soluble and active in vivo when administered in saline. The present investigation demonstrated that hydrochloride salts of numerous substituted butyryloxy esters are water-soluble and highly potent. The substitutions include piperidine, piperazine, and alkyl-substituted amino moieties. It was also discovered that incorporation of a nitrogenous moiety in the alkyl side chain increased the pharmacological potency of tetrahydrocannabinol. For example, an analog containing a pyrazole in the side chain (O-2545) was found to have high affinity and efficacy at cannabinoid 1 (CB(1)) and CB(2) receptors, and when dissolved in saline, it was highly efficacious when administered either intravenously or intracerebroventricularly to mice. A series of carboxamido and carboxylic acid amide analogs exhibited high pharmacological potency, but their hydrochloride salts were not water-soluble. On the other hand, incorporation of imidazoles into the terminus of the side chain led to water-soluble hydrochloride salts that were highly potent when administered in saline to laboratory animals. It is now possible to conduct cannabinoid research with agonists that are water-soluble and thus obviating the need of solubilizing agents.
Asunto(s)
Benzopiranos/farmacología , Cannabinoides/farmacología , Imidazoles/farmacología , Animales , Benzopiranos/administración & dosificación , Benzopiranos/química , Benzopiranos/metabolismo , Cannabinoides/administración & dosificación , Cannabinoides/química , Cannabinoides/metabolismo , Inhibidores Enzimáticos del Citocromo P-450 , Estabilidad de Medicamentos , Inhibidores Enzimáticos/farmacología , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Imidazoles/administración & dosificación , Imidazoles/química , Imidazoles/metabolismo , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Receptor Cannabinoide CB1/efectos de los fármacos , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/efectos de los fármacos , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-ActividadRESUMEN
A series of 3-phenoxypropyl piperidine analogues have been discovered as novel ORL1 receptor agonists. Structure-activity relationships have been explored around the 3-phenoxypropyl region with several potent and selective analogues identified.