Recent Medicinal Chemistry

Two recent communications described the hit-to-lead optimization which ensued from the original screening hit 10 [82,83]. From this research, four new 

Indolopiperidines were described as CCR2 antagonists, and compound 25 was reported to be potent (CCR2 Bnd Kj = 50 nM) and selective versus CCR5. However, it also displayed unwanted activity at the 5-HT and dopaminergic receptors [100]. Important functionality included the phenol (giving a 10-fold 

Several patents claiming aryl sulfonamides have recently appeared [117-121], In the first, compound 43 was described to be effective in the rat collagen-induced arthritis model when dosed at 100 mpk (s.c., q.d., from day 9-17) [117]. This patent also reported that compound 44 significantly inhibited the number of monocytes recruited following thioglycolate injection in a rat peritonitis model. Two other patent applications describe sulfonamides 45 [120] and 46 [121] as CCR2 antagonists. 

Multiple new series of CCR2 small molecule antagonists have been described in the recent patent and peer-reviewed literature. Importantly, the diversity of structural classes recognized as CCR2 antagonists has increased. These chemical advances should allow the scientific community to test adequately the hypothesis that CCR2 plays a key role in human inflammatory disease. 

Miyazaki, O. Yoshie, M. Nose and S. Fujita, Arthritis Rheum., 2003, 48, 2555. 

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