Patents on Small CXCR3 Antagonists

Piperidinyl-Amides. Merck has described a compound dass broadly centered around a piperidinylamide linked to a heteroaromatic spacer [88-90]. Affinities ( I-CXCLIO) and functional activities (chemotaxis, CXCLIO) are reported to be as low as 1 nM. Arbitrarily selected members are pyridine 33 [90], thiazole 34 [89] and thiazole 35 [88]. One publidy described member of the thiazole class is coded MRL-957 with, however, undisdosed structure. In peripheral blood mononuclear cells expressing hCXCR3, MRL-957 efficiently blocks chemotaxis by CXCLIO (ICso = 6.9nM) and CXCLll (ICso = 57.4nM) [42]. 

Piperazinyl-Piperidines. Schering-Plough has filed many patents describing a piper-azinyl-piperidine scaffold, a very general structure of which is shown as 36. It is of interest to point out that a number of compounds within this class has subnanomolar affinities and as such this class appears to be one of the most active CXCR3 series known. For example, 37-39 all have Ki = 0.2nM ( [.cxCLlO) [91-93]. 

Imidazolium Salts. SmithKlineBeecham has patented permanently charged imida-zolium salts as antagonists [97]. In independent studies, one member of this class (44) was investigated in detail [58]. It displays a fCi value of 251 nM ( I-CXCLIO) and exhibits noncompetitive antagonistic behavior on CXCR3. 

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