New substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were obtained by introducing of either unbranched or branched aliphatic chains at the 3-carboxamide nitrogen atom of previously reported CB1 receptor antagonists/inverse agonists. Synthesis of new compounds was performed by coupling reaction of the appropriate carboxylic acid with the amine in the presence of EDC/HOBT using Büchi Syncore reactor. New derivatives showed potent affinity for the human recombinant receptor hCB1 at nanomolar concentrations. n-Alkyl carboxamides brought out different SARs from the branched subgroup. Docking experiments and molecular dynamics simulations explained the potent hCB1 binding affinity of the new compounds. Pharmacokinetic studies performed in the rat after administration of 1-(2,4-dichlorophenyl)-N-hexyl-4-methyl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamide (Ki-hCB1 = 124.1 nM; Ki-hCB2 = 383.3 nM; SI (Ki-hCB2/Ki-hCB1) = 3.09) highlighted that this compound was able to reach significant plasma and brain concentrations supporting further the centrally mediated anorectic effect elicited after acute administration. References Silvestri, R., et al., 2008. Synthesis, cannabinoid receptor affinity and molecular modeling studies of substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides. J Med Chem, 51 (6), 3841-3855. Silvestri, R., et al., 2009. Synthesis, cannabinoid receptor affinity, molecular modeling studies and in vivo pharmacological evaluation of new substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides. 2. Effect of the 3-carboxamide substituent on the affinity and selectivity profile. Bioorg Med Chem, 17 (15), 5549-5564.
New N-Alkyl 1-Aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides as potent cannabinoid receptor ligands / LA REGINA, Giuseppe; Piscitelli, Francesco; Gatti, Valerio; Colombo, G.; DI MARZO, V.; Corelli, F.; Lavecchia, A.; Novellino, E.; Silvestri, Romano. - (2010), pp. 98-98. (Intervento presentato al convegno XX National Meetings on Medicinal Chemistry tenutosi a Abano Terme - Padova, Italy).
New N-Alkyl 1-Aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides as potent cannabinoid receptor ligands
LA REGINA, GIUSEPPE
;PISCITELLI, FRANCESCO;GATTI, VALERIO;SILVESTRI, Romano
2010
Abstract
New substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were obtained by introducing of either unbranched or branched aliphatic chains at the 3-carboxamide nitrogen atom of previously reported CB1 receptor antagonists/inverse agonists. Synthesis of new compounds was performed by coupling reaction of the appropriate carboxylic acid with the amine in the presence of EDC/HOBT using Büchi Syncore reactor. New derivatives showed potent affinity for the human recombinant receptor hCB1 at nanomolar concentrations. n-Alkyl carboxamides brought out different SARs from the branched subgroup. Docking experiments and molecular dynamics simulations explained the potent hCB1 binding affinity of the new compounds. Pharmacokinetic studies performed in the rat after administration of 1-(2,4-dichlorophenyl)-N-hexyl-4-methyl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamide (Ki-hCB1 = 124.1 nM; Ki-hCB2 = 383.3 nM; SI (Ki-hCB2/Ki-hCB1) = 3.09) highlighted that this compound was able to reach significant plasma and brain concentrations supporting further the centrally mediated anorectic effect elicited after acute administration. References Silvestri, R., et al., 2008. Synthesis, cannabinoid receptor affinity and molecular modeling studies of substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides. J Med Chem, 51 (6), 3841-3855. Silvestri, R., et al., 2009. Synthesis, cannabinoid receptor affinity, molecular modeling studies and in vivo pharmacological evaluation of new substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides. 2. Effect of the 3-carboxamide substituent on the affinity and selectivity profile. Bioorg Med Chem, 17 (15), 5549-5564.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
