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Identification of Morpholino-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-ones as Nonsteroidal Mineralocorticoid Antagonists

Identification of Morpholino-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-ones as Nonsteroidal Mineralocorticoid Antagonists

David W Piotrowski, Kentaro Futatsugi, Agustin Casimiro-Garcia, Liuqing Wei, Matthew F Sammons, Michael Herr, Wenhua Jiao, Sophie Y Lavergne, Steven B Coffey, Stephen W Wright, Kun Song, Paula M Loria, etc.

J Med Chem. 2018 Feb 8;61(3):1086-1097.

PMID: 29300474

Abstract:

A novel series of morpholine-based nonsteroidal mineralocorticoid receptor antagonists is reported. Starting from a pyrrolidine HTS hit 9 that possessed modest potency but excellect selectivity versus related nuclear hormone receptors, a series of libraries led to identification of morpholine lead 10. After further optimization, cis disubstituted morpholine 22 was discovered, which showed a 45-fold boost in binding affinity and corresponding functional potency compared to 13. While 22 had high clearance in rat, it provided sufficient exposure at high doses to favorably assess in vivo efficacy (increased urinary Na+/K+ ratio) and safety. In contrast to rat, the dog and human MetID and PK profiles of 22 were adequate, suggesting that it could be suitable as a potential clinical asset.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP499193565	4-(3-Trimethylsilanylethynyl-pyridin-2-yl)-morpholine		499193-56-5	Price

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