代谢型谷氨酸异二聚体正变构调节剂发现与优化中的挑战

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

作者信息

Fulton Mark Gallant, Loch Matthew Thomas, Cuoco Caroline Anne, Rodriguez Alice Lambert, Days Emily, Vinson Paige Newton, Kozek Krystian Andrezej, Weaver Charles David, Blobaum Anna Louise, Conn Peter Jeffrey, Niswender Colleen Marie, Lindsley Craig William

机构信息

Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.

Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.

出版信息

Lett Drug Des Discov. 2019 Dec;16(12):1387-1394. doi: 10.2174/1570180815666181017131349.

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.

背景

本文描述了在发现和优化代谢型谷氨酸受体2/4（mGlu2/4）异二聚体正向变构调节剂（PAM）过程中所面临的挑战。

方法

基于VU0155041（一种mGlu4同二聚体和mGlu2/4异二聚体的PAM）的初步尝试，得到了难以处理的平坦构效关系，这阻碍了研究进展。对1152种FDA批准药物的筛选发现，已批准的黄嘌呤氧化酶抑制剂非布索坦是mGlu异二聚体的一种中等效力的PAM（EC = 3.4 μM），但存在外周限制（大鼠K = 0.03）。对这一命中化合物的优化得到了效力提高（ECs <800 nM）和中枢神经系统渗透性改善（大鼠Kp >，增加约100倍）的PAM。