ABSTRACT
To identify compounds with strong mPGES-1 inhibitory activity and clear in vitro ADME profile, we optimized the lead compound 1 by carrying our substitutions at the C(7)- and C(8)-positions. Replacement of the bromine atom of 1 with various substituents led to identification of the phenyl group as the best C(7)-substituent giving strong inhibitory activity with good in vitro ADME profile. Further SAR examination on both the C(2)- and the C(7)-phenyl groups provided compound 39 as the best candidate for further development. Compound 39 exhibited strong mPGES-1 inhibitory activity (IC50=4.1 nM), potent cell-based functional activity (IC50=33 nM) with good mPGES-1 selectivity (over 700-fold), excellent in vitro ADME profile, and good oral absorption in rat PK study.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Imidazoles/chemical synthesis , Prostaglandin-Endoperoxide Synthases/chemistry , Quinolones/chemical synthesis , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Biological Availability , Cytochrome P-450 Enzyme System/chemistry , Cytochrome P-450 Enzyme System/metabolism , Drug Discovery , Drug Stability , Enzyme Inhibitors/chemistry , HEK293 Cells , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Inhibitory Concentration 50 , Prostaglandin-E Synthases , Prostaglandin-Endoperoxide Synthases/metabolism , Quinolones/chemistry , Quinolones/pharmacology , Rats , Sensitivity and Specificity , Structure-Activity RelationshipABSTRACT
We have previously reported 7-bromo-2-(2-chrolophenyl)-imidazoquinolin-4(5H)-one (1) as a novel potent mPGES-1 inhibitor. To clarify the essential functional groups of 1 for inhibition of mPGES-1, we investigated this compound structure-activity relationship following substitution at the C(4)-position and N-alkylation at the N(1)-, the N(3)-, and the N(5)-positions of 1. To prepare the target compounds, we established a good methodology for selective N-alkylation of the imidazoquinolin-4-one, that is, selective alkylation of 1 at the N(3)- and N(5)-positions was achieved by use of an appropriate base and introduction of a protecting group at the nitrogen atom in the imidazole part, respectively. Replacement of the C(4)-oxo group with nitrogen- or sulfur- linked substituents gave decreased inhibitory activity for mPGES-1, and introduction of alkyl groups on the nitrogen atom at the N(1)-, the N(3)-, and the N(5)-positions resulted in even larger loss of inhibitory activity. These results revealed that the C(4)-oxo group, and the hydrogen atoms at the N(5)-position and the imidazole part were the best substituents.
Subject(s)
Imidazoles/chemistry , Imidazoles/pharmacology , Intramolecular Oxidoreductases/antagonists & inhibitors , Quinolines/chemistry , Quinolines/pharmacology , Alkylation , HEK293 Cells , Humans , Imidazoles/chemical synthesis , Intramolecular Oxidoreductases/metabolism , Prostaglandin-E Synthases , Quinolines/chemical synthesisABSTRACT
The imidazoquinoline derivative 1 was found as a novel mPGES-1 inhibitor. Optimization of 1 led to the identification of the 2-chlorophenyl group at the C(2)-position and the quinolone structure at the C(4)-position. Compound 33, the most potent synthesized compound, showed excellent mPGES-1 inhibition (IC(50)=9.1nM) with high selectivity (>1000-fold) over both COX-1 and COX-2.
Subject(s)
Enzyme Inhibitors/pharmacology , Intramolecular Oxidoreductases/antagonists & inhibitors , Microsomes/enzymology , Quinolones/chemistry , Ammonia/chemistry , Animals , Chemistry, Pharmaceutical/methods , Cyclooxygenase 1/biosynthesis , Cyclooxygenase 2/biosynthesis , Drug Design , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Prostaglandin-E Synthases , Structure-Activity RelationshipABSTRACT
In this study, we have investigated the roles of substituents on the terminal phenyl ring at the C(4)-position of the quinazoline core to complete the structure-activity relationships (SARs) of our NF-kappa B activation inhibitors. Among them, compound 12j afforded highly potent inhibitory activity toward NF-kappa B transcriptional activation with IC(50) value of 2 nM, along with an excellent in vivo efficacy by reducing the edema formation seen in carrageenin-induced inflammation of the rat hind paw.
Subject(s)
Aminoquinolines/chemistry , NF-kappa B/antagonists & inhibitors , Quinazolines/chemistry , Aminoquinolines/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Carrageenan , Edema/chemically induced , Edema/drug therapy , Inflammation/chemically induced , Inhibitory Concentration 50 , NF-kappa B/metabolism , Quinazolines/pharmacology , Rats , Spleen/cytology , Spleen/drug effects , Spleen/growth & development , Structure-Activity Relationship , Transcriptional Activation/drug effects , Tumor Necrosis Factor-alpha/metabolismABSTRACT
We disclose here a new structural class of low-molecular-weight inhibitors of NF-kappa B activation that were designed and synthesized by starting from quinazoline derivative 6a. Structure-activity relationship (SAR) studies based on 6a elucidated the structural requirements essential for the inhibitory activity toward NF-kappa B transcriptional activation, and led to the identification of the 6-amino-4-phenethylaminoquinazoline skeleton as the basic framework. In this series of compounds, 11q, containing the 4-phenoxyphenethyl moiety at the C(4)-position, showed strong inhibitory effects on both NF-kappa B transcriptional activation and TNF-alpha production. Furthermore, 11q exhibited an anti-inflammatory effect on carrageenin-induced paw edema in rats.
Subject(s)
NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Quinazolines/chemistry , Quinazolines/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Carrageenan/toxicity , Edema/chemically induced , Edema/drug therapy , Hindlimb , Humans , Inhibitory Concentration 50 , Jurkat Cells , Male , Mice , Mice, Inbred BALB C , Rats , Spleen/cytology , Spleen/drug effects , Spleen/growth & development , Structure-Activity Relationship , Transcriptional Activation/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
In the present study, we have found that mono-unsaturated linear-chain fatty acids in the cis configuration with C(18) hydrocarbon chains (i.e. oleic acid) strongly inhibited the activity of human telomerase in a cell-free enzymic assay, with an IC(50) value of 8.6 microM. Interestingly, fatty acids with hydrocarbon chain lengths below 16 or above 20 carbons substantially decreased the potency of inhibition of telomerase. Moreover, the cis-mono-unsaturated C(18) linear-chain fatty acid oleic acid was the strongest inhibitor of all the fatty acids tested. A kinetic study revealed that oleic acid competitively inhibited the activity of telomerase ( K (i)=3.06 microM) with respect to the telomerase substrate primer. The energy-minimized three-dimensional structure of the linear-chain fatty acid was calculated and modelled. A molecule width of 11.53-14.26 A (where 1 A=0.1 nm) in the C(16) to C(20) fatty acid structure was suggested to be important for telomerase inhibition. The three-dimensional structure of the telomerase active site (i.e. the substrate primer-binding site) appears to have a pocket that could bind oleic acid, with the pocket being 8.50 A long and 12.80 A wide.