ABSTRACT
Optimization starting with our lead compound 1 (IC(50)=4.9 nM) led to the identification of pyrrolidinyl phenylurea derivatives. Further modification toward improvement of the bioavailability provided (R)-1-(1-((6-fluoronaphthalen-2-yl)methyl)pyrrolidin-3-yl)-3-(2-(2-hydroxyethoxy)phenyl)urea 32 (IC(50)=1.7 nM), a potent and orally active CCR3 antagonist.
Subject(s)
Phenylurea Compounds/chemistry , Pyrrolidines/chemistry , Receptors, CCR3/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Half-Life , Macaca fascicularis , Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/pharmacokinetics , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Receptors, CCR3/metabolismABSTRACT
The synthesis and structure-activity relationships of ureas as CCR3 antagonists are described. Optimization starting with lead compound 2 (IC(50)=190 nM) derived from initial screening hit compound 1 (IC(50)=600 nM) led to the identification of (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide 27 (IC(50)=4.9 nM) as a potent CCR3 antagonist.
Subject(s)
Receptors, CCR3/antagonists & inhibitors , Urea/analogs & derivatives , Drug Evaluation, Preclinical , Humans , Naphthalenes/chemical synthesis , Naphthalenes/chemistry , Naphthalenes/metabolism , Proline/chemistry , Protein Binding , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Pyrrolidines/metabolism , Receptors, CCR3/metabolism , Structure-Activity Relationship , Urea/chemical synthesis , Urea/metabolismABSTRACT
We report the discovery and structure-activity relationship of 2,6-disubstituted pyrazines, which are potent and selective CK2 inhibitors. Lead compound 1 was identified, and derivatives were prepared to develop potent inhibitory activity. As a result, we obtained compound 7, which was the smallest unit that retained potency. Then, introducing an aminoalkyl group at the 6-position of the indazole ring resulted in improved efficacy in both enzymatic and cell-based CK2 inhibition assays. Moreover, compound 13 showed selectivity against other kinases and in vivo efficacy in a rat nephritis model. These results show that 2,6-disubstituted pyrazines have potential as therapeutic agents for nephritis.
Subject(s)
Casein Kinase II/antagonists & inhibitors , Indazoles/chemistry , Protein Kinase Inhibitors/chemistry , Pyrazines/chemistry , Animals , Binding Sites , Casein Kinase II/metabolism , Computer Simulation , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Indazoles/chemical synthesis , Indazoles/therapeutic use , Injections, Intraperitoneal , Nephritis/drug therapy , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/therapeutic use , Protein Structure, Tertiary , Pyrazines/chemical synthesis , Pyrazines/therapeutic use , Rats , Structure-Activity RelationshipABSTRACT
Our laboratory has identified several acrylamide derivatives with potent CCR3 inhibitory activity. In the present study, we evaluated the in vitro metabolic stability (CL(int); mL/min/kg) of these compounds in human liver microsomes (HLMs), and assessed the relationship between their structures and CL(int) values. Among the compounds identified, N-{(3R)-1-[(6-fluoro-2-naphthyl)methyl]pyrrolidin-3-yl}-2-[1-(2-hydroxybenzoyl)piperidin-4-ylidene]acetamide (30j) was found to be a potent inhibitor (IC(50)=8.4nM) with a high metabolic stability against HLMs.
Subject(s)
Acetamides/chemical synthesis , Acrylamides/chemistry , Anti-Allergic Agents/chemical synthesis , Naphthalenes/chemical synthesis , Receptors, CCR3/antagonists & inhibitors , Acetamides/chemistry , Acetamides/pharmacology , Acrylamides/chemical synthesis , Acrylamides/pharmacokinetics , Animals , Anti-Allergic Agents/chemistry , Anti-Allergic Agents/pharmacokinetics , Haplorhini , Humans , Mice , Microsomes, Liver/metabolism , Naphthalenes/chemistry , Naphthalenes/pharmacology , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Receptors, CCR3/metabolism , ThermodynamicsABSTRACT
In our previous study on discovering novel types of CCR3 antagonists, we found a fluoronaphthalene derivative (1) that exhibited potent CCR3 inhibitory activity with an IC(50) value of 20 nM. However, compound 1 also inhibited human cytochrome P450 2D6 (CYP2D6) with an IC(50) value of 400 nM. In order to reduce its CYP2D6 inhibitory activity, we performed further systematic structural modifications on 1. In particular, we focused on reducing the number of lipophilic moieties in the biphenyl part of 1, using ClogD(7.4) values as the reference index of lipophilicity. This research led to the identification of N-{(3-exo)-8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl}-3-(piperidin-1-ylcarbonyl)isonicotinamide 1-oxide (30) which showed comparable CCR3 inhibitory activity (IC(50)=23 nM) with much reduced CYP2D6 inhibitory activity (IC(50)=29,000 nM) compared with 1.
Subject(s)
Cytochrome P-450 CYP2D6 Inhibitors , Drug Design , Hydrocarbons, Fluorinated/pharmacology , Naphthalenes/pharmacology , Receptors, CCR3/antagonists & inhibitors , Calcium/chemistry , Calcium/metabolism , Cytoplasm/chemistry , Cytoplasm/metabolism , Humans , Hydrocarbons, Fluorinated/chemical synthesis , Inhibitory Concentration 50 , Naphthalenes/chemical synthesis , Receptors, CCR3/metabolism , Structure-Activity RelationshipABSTRACT
A novel class of potent CCR3 receptor antagonists were designed and synthesized starting from N-{1-[(6-fluoro-2-naphthyl)methyl]piperidin-4-yl}benzamide (1),which was found by subjecting our chemical library to high throughput screening (HTS). The CCR3 inhibitory activity of the synthesized compounds against eotaxin-induced Ca(2+) influx was evaluated using CCR3-expressing preB cells. Systematic chemical modifications of 1 revealed that the 6-fluoro-2-naphthylmethyl moiety was essential for CCR3 inhibitory activity in this new series of CCR3 antagonists. Further structural modifications of the benzamide and piperidine moieties of 1 led to the identification of exo-N-{8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3- yl}biphenyl-2-carboxamide [corrected] (31) as a potent CCR3 antagonist with an IC(50) value of 0.020 microM.
