IV. Discovery of CXCR3 antagonists substituted with heterocycles as amide surrogates: improved PK, hERG and metabolic profiles.

Abstract The structure–human CXCR3 binding affinity relationship of a series of pyridyl/pyrazinyl–piperazinyl-piperidine derivatives were explored with a focus to improve PK, hERG and metabolic profiles. Several small heterocycles were identified as amide surrogates, which minimized many potential metabolite issues. During the course of SAR development, we have observed the additive effect of desirable functional groups to improve hERG and PK profiles which lead to the discovery of many clinically developable CXCR3 antagonists with excellent overall profile.