Soluble Guanylate Cyclase Stimulators For The Treatment Of Hypertension: Discovery Of Mk-2947

Linda Brockunier, John Stelmach, Jian Guo, Tracy Spencer, Keith Rosauer,Alka Bansal, Sheng-Jian Cai,Nancy Chen, John Cummings,Li Huang,Timothy Johnson, Sonia Levesque,Lin Luo,Kevin Maloney,Joseph Metzger, Christopher Mortko, Karen Ortega,Lee-Yuh Pai, Antonio Pereira,Gino Salituro,Jackie Shang, Cherrie Shepherd, Shiyao Sherrie Xu, Qifeng Yang,Jisong Cui,Sophie Roy,Emma Parmee,Subharekha Raghavan

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS（2020）

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Abstract

The NO-sGC-cGMP signaling pathway plays an important role in the cardiovascular system. Loss of nitric oxide tone or impaired signaling has been associated with cardiovascular diseases, such as hypertension, pulmonary hypertension and heart failure. Direct activation of sGC enzyme independent of NO represents a novel approach for modulating NO signaling with tremendous therapeutic potential. Herein, we describe the design of a structurally novel class of heme-dependent sGC stimulators containing the 3,3-dimethylpyrrolidin-2-one moiety which resulted in the identification of the potent, selective stimulator 30 (MK-2947) for the treatment of hypertension.

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Key words

Soluble guanylate cyclase, Nitric oxide, Heme-dependent sGC stimulators, sGC stimulators, Hypertension, cGMP, SHR, MK-2947, NO-sGC-cGMP

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