24919-40-2Relevant articles and documents
Identification of an Orally Bioavailable, Brain-Penetrant Compound with Selectivity for the Cannabinoid Type 2 Receptor
Ashpole, Nicole,Ibrahim, Mohamed A.,Ospanov, Meirambek,Paris, Jason J.,Rimoldi, John M.,Ross, Samir A.,Shilabin, Abbas G.,Sulochana, Suresh P.,Walker, Larry
, (2022/01/24)
Modulation of the endocannabinoid system (ECS) is of great interest for its therapeutic relevance in several pathophysiological processes. The CB2 subtype is largely localized to immune effectors, including microglia within the central nervous system, where it promotes anti-inflammation. Recently, a rational drug design toward precise modulation of the CB2 active site revealed the novelty of Pyrrolo[2,1-c][1,4]benzodiazepines tricyclic chemotype with a high conformational similarity in comparison to the existing leads. These compounds are structurally unique, confirming their chemo-type novelty. In our continuing search for new chemotypes as selective CB2 regulatory molecules, following SAR approaches, a total of 17 selected (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs were synthesized and tested for their ability to bind to the CB1 and CB2 receptor orthosteric sites. A competitive [3H]CP-55,940 binding screen revealed five compounds that exhibited >60% displace-ment at 10 μM concentration. Further concentration-response analysis revealed two compounds, 4k and 4q, as potent and selective CB2 ligands with sub-micromolar activities (Ki = 146 nM and 137 nM, respectively). In order to support the potential efficacy and safety of the analogs, the oral and intravenous pharmacokinetic properties of compound 4k were sought. Compound 4k was orally bioavailable, reaching maximum brain concentrations of 602 ± 162 ng/g (p.o.) with an elimination half-life of 22.9 ± 3.73 h. Whether administered via the oral or intravenous route, the elimination half-lives ranged between 9.3 and 16.7 h in the liver and kidneys. These compounds represent novel chemotypes, which can be further optimized for improved affinity and selectivity toward the CB2 receptor.
The synthesis and anti-inflammatory evaluation of 1,2,3-triazole linked isoflavone benzodiazepine hybrids
Menghere?, Gabriel,Olajide, Olumayokun,Hemming, Karl
supporting information, p. 306 - 321 (2021/02/05)
Copper catalyzed azide-alkyne cycloaddition was used for the first time to access a small series of eight novel 1,2,3-triazole linked isoflavone benzodiazepine hybrids. As part of this work, a previously unreported alkyne substituted pyrrolo[1,4]benzodiaz
Low-valent titanium-mediated enantioselective synthesis of quinazolinone alkaloids circumdatins F, H, and analogs
Luo, Shi-Peng,Geng, Hui,Wang, Yu,Huang, Pei-Qiang
, p. 646 - 654 (2015/06/25)
We report the concise and protecting-group-free enantioselective total syntheses of circumdatins F and H. In view of the extreme importance of analogs of quinazolinone alkaloids in drug research and discovery, four analogs of bioactive quinazolinobenzodiazepine alkaloids, including demethoxycircumdatin H (12) and N-demethylbenzomalvin A (13), have been synthesized. The method is based on the low-valent titanium-promoted intramolecular reductive coupling of imides with o-nitrobenzimides, which yielded quinazolino[3,2-a][1,4]benzodiazepines under mild conditions. In addition, heptacyclic dehydraasperlicin E (16) has been synthesized from asperlicin C by a NCS-mediated dehydra-cyclization reaction.
