Addressing hERG activity while maintaining favorable potency, selectivity and pharmacokinetic properties of PPARδ modulators

Bioorg Med Chem Lett. 2020 Feb 15;30(4):126928. doi: 10.1016/j.bmcl.2019.126928.

Bharat Lagu ¹, Ramesh S Senaiar ², Arthur F Kluge ³, B Mallesh ², M Ramakrishna ², Raveendra Bhat ², Michael A Patane ³

Affiliations

1 Mitobridge, Inc. (a wholly owned subsidiary of Astellas Pharma.), 1030 Massachusetts Avenue, Cambridge, MA 02138, USA. Electronic address: Bharat.lagu@astellas.com.
2 Aurigene Discovery Technologies, Ltd., Bengaluru, India.
3 Mitobridge, Inc. (a wholly owned subsidiary of Astellas Pharma.), 1030 Massachusetts Avenue, Cambridge, MA 02138, USA.

PMID: 31889664 DOI: 10.1016/j.bmcl.2019.126928

Abstract

One of the most commonly used strategies to reduce hERG (human ether-a-go-go) activity in the drug candidates is introduction of a carboxylic acid group. During the optimization of PPARδ modulators, some of the compounds containing a carboxylic acid were found to inhibit the hERG channel in a patch clamp assay. By modifying the basicity of the imidazole core, potent and selective PPARδ modulators that do not inhibit hERG channel were identified. Some of the modulators have excellent pharmacokinetic profiles in mice.

Keywords

PPARδ modulators; Patch clamp assay; TPSA; cLogP; hERG; pKa.

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