RESUMO
Ferrocene analogs of known fatty acid amide hydrolase inhibitors and CB2 ligands have been synthesized and characterized spectroscopically and crystallographically. The resulting bio-organometallic isoxazoles were assayed for their effects on CB1 and CB2 receptors as well as on fatty acid amide hydrolase. None had any fatty acid amide hydrolase activity but compound 3, 5-(2-(pentyloxy)phenyl)-N-ferrocenylisoxazole-3-carboxamide, was found to be a potent CB2 ligand (Ki = 32.5 nM).
Assuntos
Compostos Ferrosos/química , Metalocenos/química , Receptor CB2 de Canabinoide/química , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Sítios de Ligação , Compostos Ferrosos/síntese química , Compostos Ferrosos/metabolismo , Humanos , Ligantes , Metalocenos/síntese química , Metalocenos/metabolismo , Conformação Molecular , Simulação de Acoplamento Molecular , Ligação Proteica , Receptor CB1 de Canabinoide/química , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismoRESUMO
A series of novel oxazolo[5,4-d]pyrimidines was designed via a scaffold hopping strategy and synthesized through a newly developed approach. All these compounds were evaluated for their biological activity toward CB1/CB2 cannabinoid receptors, their metabolic stability in mice liver microsomes and their cytotoxicity against several cell lines. Eight compounds have been identified as CB2 ligands with Ki values less than 1⯵M. It is noteworthy that 2-(2-chlorophenyl)-5-methyl-7-(4-methylpiperazin-1-yl) oxazolo[5,4-d]pyrimidine 47 and 2-(2-chlorophenyl)-7-(4-ethylpiperazin-1-yl)- 5-methyloxazolo[5,4-d]pyrimidine 48 showed CB2 binding affinity in the nanomolar range and significant selectivity over CB1 receptors. Interestingly, functionality studies imply that they behave as competitive neutral antagonists. Moreover, all tested compounds are devoid of cytotoxicity toward several cell lines, including Chinese hamster ovary cells (CHO) and human colorectal adenocarcinoma cells HT29.
Assuntos
Oxazóis/farmacologia , Pirimidinas/farmacologia , Receptor CB2 de Canabinoide/antagonistas & inibidores , Animais , Ligação Competitiva/efeitos dos fármacos , Células CHO , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cricetulus , Relação Dose-Resposta a Droga , Células HT29 , Humanos , Masculino , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Oxazóis/síntese química , Oxazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel and original strategy to obtain rapidly a large diversity of C-8 and N-9 substituted purines was developed. The present procedure describes annulation reactions in one or two steps starting from 5-aminoimidazole-4-carbonitriles 1-8 in moderate to good yields. 8,9-Disubstituted-6,9-dihydro-1H-purin-6-ones 9-14, 6-amino-8,9-disubstituted-3,9-dihydro-2H-purin-2-ones 15-20, 8,9-disubstituted-3,9-dihydro-2H-purin-2,6-diamines 21-24 and 6-imino-1-phenyl-8,9-disubstituted-6,9-dihydro-1H-purin-2-(3H)-ones 25-26 were synthesized in one step using formic acid, urea, guanidine carbonate, and phenylisocyanate, respectively, whereas 8,9-disubstituted-9H-purin-6-amines 27-31 and 6-imino-8,9-disubstituted-6,9-dihydro-1H-purin-1-amines 32-33 were obtained in two steps using formamide and hydrazine, respectively.
