ABSTRACT
A series of 3-substituted 1,5-diarylpyrroles bearing a nitrooxyalkyl side chain linked to different spacers were designed. New classes of pyrrole-derived nitrooxyalkyl inverse esters, carbonates, and ethers (7-10) as COX-2 selective inhibitors and NO donors were synthesized and are herein reported. By taking into account the metabolic conversion of nitrooxyalkyl ethers (9, 10) into corresponding alcohols, derivatives 17 and 18 were also studied. Nitrooxy derivatives showed NO-dependent vasorelaxing properties, while most of the compounds proved to be very potent and selective COX-2 inhibitors in in vitro experimental models. Further in vivo studies on compounds 9a,c and 17a highlighted good anti-inflammatory and antinociceptive activities. Compound 9c was able to inhibit glycosaminoglycan (GAG) release induced by interleukin-1ß (IL-1ß), showing cartilage protective properties. Finally, molecular modeling and (1)H- and (13)C-NMR studies performed on compounds 6c,d, 9c, and 10b allowed the right conformation of nitrooxyalkyl ester and ether side chain of these molecules within the COX-2 active site to be assessed.
Subject(s)
Analgesics/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase 2 Inhibitors/pharmacology , Nitric Oxide Donors/pharmacology , Pyrroles/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/drug effects , Cyclooxygenase 2 Inhibitors/chemistry , Ethers/chemical synthesis , Ethers/pharmacology , Humans , Inhibitory Concentration 50 , Mice , Osteoarthritis/drug therapy , Pyrroles/chemical synthesis , Pyrroles/chemistry , RatsABSTRACT
The CB(2) receptor activation can be exploited for the treatment of diseases such as chronic pain and tumors of immune origin, devoid of psychotropic activity. On the basis of our already reported 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives, new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the human CB(1) and CB(2) cannabinoid receptors. Some of the reported compounds showed a subnanomolar CB(2) affinity with a CB(1)/CB(2) selectivity ratio greater than 200 (compounds 6, 12, cis-12, 13, and cis-13). Further studies revealed that compound 12, which presented benzyl and carboxy-4-methylcyclohexylamide substituents bound in the 1 and 3 positions, exerted a CB(2)-mediated inhibitory action on immunological human basophil activation. On the human T cell leukemia line Jurkat the same derivative induced a concentration-dependent decrease of cell viability. The obtained results suggest that 1,8-naphthyridin-2(1H)-on-3-carboxamides represent a new scaffold very suitable for the development of new promising CB(2) agonists.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Drug Design , Naphthyridines/chemical synthesis , Naphthyridines/pharmacology , Receptor, Cannabinoid, CB2/agonists , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Humans , Jurkat Cells , Models, Molecular , Molecular Structure , Naphthyridines/chemistry , Receptor, Cannabinoid, CB1/agonists , Structure-Activity RelationshipABSTRACT
A series of new 1,8-naphthyridine and quinoline derivatives were synthesized and evaluated for their cannabinoid receptor affinity. In particular, compounds 2, 5, 11, and 13 showed a high CB(2) affinity and CB(2) versus CB(1) selectivity, in agreement with molecular modeling studies. Furthermore, compound 2 also exhibited in vivo antinociceptive effects.
Subject(s)
Naphthyridines/chemistry , Quinolines/chemistry , Receptor, Cannabinoid, CB2/agonists , Animals , Cell Line , Humans , Mice , Naphthyridines/pharmacology , Pain Measurement/drug effects , Pain Measurement/methods , Quinolines/pharmacology , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/biosynthesis , Receptor, Cannabinoid, CB1/genetics , Receptor, Cannabinoid, CB1/physiology , Receptor, Cannabinoid, CB2/biosynthesis , Receptor, Cannabinoid, CB2/genetics , Receptor, Cannabinoid, CB2/physiologyABSTRACT
On the basis of docking studies carried out using the recently published cannabinoid receptor models,35 new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the cannabinoid CB1 and CB2 receptors. Compound 10, which presented p-fluorobenzyl and carboxycycloheptylamide substituents bound in the 1 and 3 positions of the 1,8-naphthyiridine-4-one nucleus, showed a high CB2 affinity with a Ki of 1.0 nM. The substitution of the naphthyridine-4-one nucleus with the quinoline-4-one system determined a general increase in CB2 affinity. In particular, the N-cyclohexyl-7-chloro-1-(2-morpholin-4-ylethyl)quinolin-4(1H)-on-3-carboxamide (40) possessed a remarkable affinity, with Ki of 3.3 nM, which was also accompanied by a high selectivity for the CB2 receptor (Ki(CB1)/Ki(CB2) ratio greater than 303). Moreover, the [35S]GTPgamma binding assay and functional studies on human basophils indicated that the 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives behaved as CB1 and CB2 receptor agonists.