Design, synthesis, and pharmacological evaluation of new neuroactive pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives with in vivo hypnotic and analgesic profile.
The present study describes the synthesis and pharmacological profiles of four novel pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives 2-5, which were structurally designed by using the sedative and analgesic drug zolpidem 1 as lead compound. The heterotricyclic system present in the target compounds 2-5 was constructed in good yields, exploiting a regioselective hetero Diels-Alder reaction of the key azabutadiene derivative 7 and functionalized N-phenylmaleimides 9-12. Additionally, we identified that 1-methyl-7-(4-nitrophenyl)-3-phenyl-3,6,7,8-tetrahydropyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8-dione derivative (LASSBio-873, 5) presented not only the most potent ability to promote sedation, which was similar to that induced by the standard benzodiazepine drug midazolam, but also potent central antinociceptive effect.
Menegatti
Ricardo
R
Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, PO Box 68023, Rio de Janeiro 21944-971, RJ, Brazil.
Silva
Gilberto M S
GM
Zapata-Sudo
Gisele
G
Raimundo
Juliana M
JM
Sudo
Roberto T
RT
Barreiro
Eliezer J
EJ
Fraga
Carlos A M
CA
D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D018755:GABA Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism; D012890:Sleep / Q000187:drug effects; D000077334:Zolpidem
D018712:Analgesics, Non-Narcotic; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives; D008024:Ligands; D011725:Pyridines; D011963:Receptors, GABA-A; D000077334:Zolpidem