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Bioorg Med Chem Lett. 2014 Feb 15;24(4):1085-8. doi: 10.1016/j.bmcl.2014.01.009. Epub 2014 Jan 11.

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

Author information

1
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: gopinadhan.anilkumar@Merck.com.
2
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
3
Ligand Pharmaceuticals, 3000 Eastpark Boulevard, Cranbury, NJ 08512, USA.

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.

KEYWORDS:

CXCR3

PMID:
24486132
DOI:
10.1016/j.bmcl.2014.01.009
[Indexed for MEDLINE]

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