2. Academic Validation
  3. Discovery of IWP-051, a Novel Orally Bioavailable sGC Stimulator with Once-Daily Dosing Potential in Humans

Discovery of IWP-051, a Novel Orally Bioavailable sGC Stimulator with Once-Daily Dosing Potential in Humans

  • ACS Med Chem Lett. 2016 Feb 24;7(5):465-9. doi: 10.1021/acsmedchemlett.5b00479.
Takashi Nakai 1,  Nicholas R Perl 1,  Timothy C Barden 1,  Andrew Carvalho 1,  Angelika Fretzen 1,  Peter Germano 1,  G-Yoon J Im 1,  Hong Jin 1,  Charles Kim 1,  Thomas W-H Lee 1,  Kimberly Long 1,  Joel Moore 1,  Jason M Rohde 1,  Renee Sarno 1,  Chrissie Segal 1,  Erik O Solberg 1,  Jenny Tobin 1,  Daniel P Zimmer 1,  Mark G Currie 1
Affiliations

Affiliation

  • 1 Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
PMID: 27190594 DOI: 10.1021/acsmedchemlett.5b00479
Abstract

In recent years, soluble Guanylate Cyclase (sGC, EC 4.6.1.2) has emerged as an attractive therapeutic target for treating cardiovascular diseases and diseases associated with fibrosis and end-organ failure. Herein, we describe our design and synthesis of a series of 4-hydroxypyrimidine sGC stimulators starting with an internally discovered lead. Our efforts have led to the discovery of IWP-051, a molecule that achieves good alignment of potency, stability, selectivity, and pharmacodynamic effects while maintaining favorable pharmacokinetic properties with once-daily dosing potential in humans.

Keywords

IWP-051; NO-independent stimulators; Soluble guanylate cyclase; heme-dependent sGC stimulators; nitric oxide; sGC.

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