ABSTRACT
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).
Subject(s)
Ferrous Compounds/chemistry , Metallocenes/chemistry , Receptor, Cannabinoid, CB2/chemistry , Amidohydrolases/antagonists & inhibitors , Amidohydrolases/metabolism , Binding Sites , Ferrous Compounds/chemical synthesis , Ferrous Compounds/metabolism , Humans , Ligands , Metallocenes/chemical synthesis , Metallocenes/metabolism , Molecular Conformation , Molecular Docking Simulation , Protein Binding , Receptor, Cannabinoid, CB1/chemistry , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolismABSTRACT
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.
Subject(s)
Oxazoles/pharmacology , Pyrimidines/pharmacology , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Animals , Binding, Competitive/drug effects , CHO Cells , Cell Proliferation/drug effects , Cells, Cultured , Cricetulus , Dose-Response Relationship, Drug , HT29 Cells , Humans , Male , Mice , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Oxazoles/chemical synthesis , Oxazoles/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity RelationshipABSTRACT
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.
