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Niswender Laboratory

Challenges in the Discovery and Optimization of mGlu Heterodimer Positive Allosteric Modulators

AUTHORS

Fulton MGMark Gallant , Loch MTMatthew Thomas , Cuoco CACaroline Anne , Rodriguez ALAlice Lambert , Days EEmily , Vinson PNPaige Newton , Kozek KAKrystian Andrezej , Weaver CDCharles David , Blobaum ALAnna Louise , Conn PJPeter Jeffrey , Niswender CMColleen Marie , Lindsley CWCraig William . Letters in drug design & discovery. 2019 12 16; 16(12). 1387-1394

ABSTRACT

Background: This article describes the challenges in the discovery and optimization of mGlu2/4 heterodimer Positive Allosteric Modulators (PAMs).

Methods: Initial forays based on VU0155041, a PAM of both the mGlu4 homodimer and the mGlu2/4 heterodimer, led to flat, intractable SAR that precluded advancement. Screening of a collection of 1,152 FDA approved drugs led to the discovery that febuxostat, an approved xanthine oxidase inhibitor, was a moderately potent PAM of the mGlu heterodimer (EC = 3.4 μM), but was peripherally restricted (rat K = 0.03). Optimization of this hit led to PAMs with improved potency (ECs <800 nM) and improved CNS penetration (rat Kp >, an ~100-fold increase).

Results: However, these new amide analogs of febuxostat proved to be either GIRK1/2 and GIRK1/4 activators (primary carboxamide congeners) or mGlu PAMs (secondary and tertiary amides) and not selective mGlu heterodimer PAMs.

Conclusion: These results required the team to develop a new screening cascade paradigm, and exemplified the challenges in developing allosteric ligands for heterodimeric receptors.

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