RESUMEN
The discovery of non-basic N'-(arylsulfonyl)pyrazoline-1-carboxamidines as 5-HT6 antagonists with unique structural features was recently disclosed. Here we describe how this structural class was further developed by addressing an unexplored interaction site of the 5-HT6 receptor. Compound 13 resulting from this effort is a highly potent and selective 5-HT6 antagonist with improved metabolic stability. It is furthermore devoid of hERG affinity. Despite its modest CNS/plasma ratio, a high brain free fraction ensured substantial exposure to allow for rodent cognition studies.
Asunto(s)
Pirazoles/farmacología , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Sulfonamidas/farmacología , Sitios de Unión/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
The synthesis, structure-activity relationship (SAR) studies and intramolecular hydrogen bonding pattern of 1,3,5-trisubstituted 4,5-dihydropyrazoles are described. The target compounds 6-18 represent a novel class of potent and selective CB(1) receptor antagonists. Based on X-ray diffraction data, the orally active 17 is shown to elicit a different intramolecular H-bonding mode as compared to ibipinabant (3) and SLV330 (4).
Asunto(s)
Fármacos Antiobesidad/síntesis química , Pirazoles/síntesis química , Receptor Cannabinoide CB1/antagonistas & inhibidores , Sulfonamidas/síntesis química , Administración Oral , Animales , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Sitios de Unión , Cristalografía por Rayos X , Humanos , Enlace de Hidrógeno , Conformación Molecular , Pirazoles/química , Pirazoles/farmacología , Ratas , Receptor Cannabinoide CB1/metabolismo , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
The synthesis and SAR of 3-alkyl-4-aryl-4,5-dihydropyrazole-1-carboxamides 1-23 and 1-alkyl-5-aryl-4,5-dihydropyrazole-3-carboxamides 24-27 as two novel cannabinoid CB(1) receptor agonist classes were described. The target compounds elicited high affinities to the CB(1) as well as the CB(2) receptor and were found to act as CB(1) receptor agonists. The key compound 19 elicited potent CB(1) agonistic and CB(2) inverse agonistic properties in vitro and showed in vivo activity in a rodent model for multiple sclerosis after oral administration.
Asunto(s)
Pirazoles/farmacología , Receptor Cannabinoide CB1/agonistas , Pirazoles/químicaRESUMEN
The cannabinoid CB(1)/CB(2) receptor subtype selectivity in the 1,2-diarylimidazole-4-carboxamide series was boosted by fine-tuning its 5-substitution pattern. The presence of the 5-methylsulfonyl group in 11 led to a greater than approximately 840-fold CB(1)/CB(2) subtype selectivity. The compounds 10, 18 and 19 were found more active than rimonabant (1) in a CB(1)-mediated rodent hypotension model after oral administration. Our findings suggest a limited brain exposure of the P-glycoprotein substrates 11, 12 and 21.
Asunto(s)
Aminoimidazol Carboxamida/análogos & derivados , Imidazoles/química , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB2/antagonistas & inhibidores , Sulfonas/química , Administración Oral , Aminoimidazol Carboxamida/síntesis química , Aminoimidazol Carboxamida/química , Aminoimidazol Carboxamida/uso terapéutico , Animales , Modelos Animales de Enfermedad , Agonismo Inverso de Drogas , Hipotensión/tratamiento farmacológico , Imidazoles/síntesis química , Imidazoles/uso terapéutico , Ratones , Ratas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/uso terapéuticoRESUMEN
The synthesis and structure-activity relationship studies of imidazoles are described. The target compounds 6-20 represent a novel chemotype of potent and CB(2)/CB(1) selective cannabinoid CB(2) receptor antagonists/inverse agonists with very high binding efficiencies in combination with favourable logP and calculated polar surface area values. Compound 12 exhibited the highest CB(2) receptor affinity (K(i)=1.03 nM) in this series, as well as the highest CB(2)/CB(1) subtype selectivity (>9708-fold).
Asunto(s)
Imidazoles/síntesis química , Imidazoles/metabolismo , Receptor Cannabinoide CB2/antagonistas & inhibidores , Receptor Cannabinoide CB2/metabolismo , Animales , Células CHO , Cannabinoides/antagonistas & inhibidores , Cannabinoides/metabolismo , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Humanos , Unión Proteica/fisiología , Relación Estructura-ActividadRESUMEN
The synthesis and structure-activity relationship studies of 1,4,5,6-tetrahydropyridazines are described. The target compounds 3-5 represent a novel class of potent and selective CB1 receptor antagonists.
Asunto(s)
Piridazinas/síntesis química , Receptor Cannabinoide CB1/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Piridazinas/química , Piridazinas/farmacología , Receptor Cannabinoide CB1/metabolismo , Relación Estructura-ActividadRESUMEN
The discovery, synthesis and structure-activity relationship (SAR) of a novel series of cannabinoid 1 (CB(1)) and cannabinoid 2 (CB(2)) receptor ligands are reported. Based on the aminoalkylindole class of cannabinoid receptor agonists, a biphenyl moiety was introduced as novel lipophilic indole 3-acyl substituent in 11-16. Furthermore, the 3-carbonyl tether was replaced with a carboxamide linker in 17-20 and the azaindole (pyrrolopyridine) nucleus was designed as indole bioisostere with improved physicochemical properties in 21-25. Through these SAR efforts, several high affinity CB(1)/CB(2) dual cannabinoid receptor ligands were identified. Indole-3-carboxamide 17 displayed single-digit nanomolar affinity and ~80 fold selectivity for CB(1) over the CB(2) receptor. The azaindoles displayed substantially improved physicochemical properties (lipophilicity; aqueous solubility). Azaindole 21 elicited potent cannabinoid activity. Cannabinoid receptor agonists 17 and 21 potently modulated excitatory synaptic transmission in an acute rat brain slice model of cannabinoid receptor-modulated neurotransmission.
Asunto(s)
Agonistas de Receptores de Cannabinoides , Indoles/química , Indoles/farmacología , Receptores de Cannabinoides/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Células CHO , Cricetinae , Humanos , Indoles/síntesis química , Ligandos , Masculino , Ratas , Ratas Wistar , Receptor Cannabinoide CB2/agonistas , Relación Estructura-ActividadRESUMEN
The 5-HT(6) receptor (5-HT(6)R) has been in the spotlight for several years regarding CNS-related diseases. We set out to discover novel, neutral 5-HT(6)R antagonists to improve off-target selectivity compared to basic amine-containing scaffolds dominating the field. High-throughput screening identified the N'-(sulfonyl)pyrazoline-1-carboxamidine scaffold as a promising neutral core for starting hit-to-lead. Medicinal chemistry, molecular modeling, small molecule NMR and X-ray crystallography were subsequently applied to optimize the leads into antagonists (compounds 1-49) displaying high 5-HT(6)R affinity with optimal off-target selectivity. Unique structural features include a pseudoaromatic system and an internal hydrogen bond freezing the bioactive conformation. While physicochemical properties and CNS availability were generally favorable, significant efforts had to be made to improve metabolic stability. The optimized structure 42 is an extremely selective, hERG-free, high-affinity 5-HT(6)R antagonist showing good human in vitro metabolic stability. Rat pharmacokinetic data were sufficiently good to enable further in vivo profiling.
Asunto(s)
Amidinas/síntesis química , Pirazoles/síntesis química , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/síntesis química , Sulfonamidas/síntesis química , Amidinas/química , Amidinas/farmacología , Animales , Células CHO , Cricetinae , Cricetulus , Cristalografía por Rayos X , Cobayas , Hepatocitos/metabolismo , Humanos , Técnicas In Vitro , Ligandos , Espectroscopía de Resonancia Magnética , Masculino , Modelos Moleculares , Unión Proteica , Pirazoles/química , Pirazoles/farmacología , Ratas , Ratas Wistar , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
Pyrazolines 7-10 were designed as novel CB(1) receptor antagonists, which exhibited improved turbidimetric aqueous solubilities. On the basis of their extended CB(1) antagonist pharmacophore, hybrid molecules exhibiting cannabinoid CB(1) receptor antagonistic as well as acetylcholinesterase (AChE) inhibiting activities were designed. The target compounds 12, 13, 20, and 21 are based on 1 (tacrine) as the AChE inhibitor (AChEI) pharmacophore and two different CB(1) antagonistic pharmacophores. The imidazole-based 20 showed high CB(1) receptor affinity (48 nM) in combination with high CB(1)/CB(2) receptor subtype selectivity (>20-fold) and elicited equipotent AChE inhibitory activity as 1. Molecular modeling studies revealed the presence of a binding pocket in the AChE enzyme which nicely accommodates the CB(1) pharmacophores of the target compounds 12, 13, 20, and 21.