Discovery, optimization, and pharmacological characterization of novel heteroaroylphenylureas antagonists of C-C chemokine ligand 2 function

Edgardo Laborde; Robert W Macsata; Fanying Meng; Brian T Peterson; Louise Robinson; Steve R Schow; Reyna J Simon; Hua Xu; Kunihisa Baba; Hideaki Inagaki; Yoshiro Ishiwata; Takahito Jomori; Yukiharu Matsumoto; Atsushi Miyachi; Takashi Nakamura; Masayuki Okamoto; Tracy M Handel; Claude C A Bernard

doi:10.1021/jm1012903

Discovery, optimization, and pharmacological characterization of novel heteroaroylphenylureas antagonists of C-C chemokine ligand 2 function

J Med Chem. 2011 Mar 24;54(6):1667-81. doi: 10.1021/jm1012903. Epub 2011 Feb 22.

Authors

Edgardo Laborde¹, Robert W Macsata, Fanying Meng, Brian T Peterson, Louise Robinson, Steve R Schow, Reyna J Simon, Hua Xu, Kunihisa Baba, Hideaki Inagaki, Yoshiro Ishiwata, Takahito Jomori, Yukiharu Matsumoto, Atsushi Miyachi, Takashi Nakamura, Masayuki Okamoto, Tracy M Handel, Claude C A Bernard

Affiliation

¹ Telik, Inc., 700 Hansen Way, Palo Alto, California 94304, United States. elaborde@telik.com

Abstract

Through the application of TRAP (target-related affinity profiling), we identified a novel class of heteroaroylphenylureas that inhibit human CCL2-induced chemotaxis of monocytes/macrophages both in vitro and in vivo. This inhibition was concentration-dependent and selective with regard to other chemokines. The compounds, however, did not antagonize the binding of (125)I-labeled CCL2 to the CCR2 receptor nor did they block CCR2-mediated signal transduction responses such as calcium mobilization. Optimization of early leads for potency and pharmacokinetic parameters resulted in the identification of 17, a potent inhibitor of chemotaxis (IC(50) = 80 nM) with excellent oral bioavailability in rats (F = 60%). Compound 17 reduced swelling and joint destruction in two rat models of rheumatoid arthritis and delayed disease onset and produced near complete resolution of symptoms in a mouse model of multiple sclerosis.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Administration, Oral
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Arthritis, Experimental / drug therapy
Arthritis, Experimental / pathology
Arthritis, Rheumatoid / drug therapy
Arthritis, Rheumatoid / pathology
Biological Availability
Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
CHO Cells
Cell Line, Tumor
Chemokine CCL2 / antagonists & inhibitors*
Chemotaxis / drug effects
Cricetinae
Cricetulus
Humans
Joints / drug effects
Joints / pathology
Macrophages / drug effects
Macrophages / physiology
Mice
Mice, Inbred ICR
Monocytes / drug effects
Monocytes / physiology
Multiple Sclerosis / drug therapy
Phenylurea Compounds / chemical synthesis*
Phenylurea Compounds / pharmacokinetics
Phenylurea Compounds / pharmacology
Radioligand Assay
Rats
Receptors, CCR2 / metabolism
Structure-Activity Relationship

Substances

1-(6-((2-(dimethylamino)ethyl)(methyl)amino)-1,3-dimethyl-1H-pyrazolo(3,4-b)pyridine-5-carbonyl)-3-(3-isopropoxyphenyl)urea
Anti-Inflammatory Agents, Non-Steroidal
Bridged Bicyclo Compounds, Heterocyclic
Chemokine CCL2
Phenylurea Compounds
Receptors, CCR2

Abstract

Publication types

MeSH terms

Substances

Grants and funding