title: Discovery of IWP-051, a Novel Orally Bioavailable sGC Stimulator with Once-Daily Dosing Potential in Humans.
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.
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakai
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Perl
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Barden
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Carvalho
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: Angelika
authors.initials: A
authors.lastname: Fretzen
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Germano
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: G-Yoon J
authors.initials: GY
authors.lastname: Im
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Jin
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: Charles
authors.initials: C
authors.lastname: Kim
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: Thomas W-H
authors.initials: TW
authors.lastname: Lee
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Long
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: Joel
authors.initials: J
authors.lastname: Moore
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Rohde
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: Renee
authors.initials: R
authors.lastname: Sarno
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: Chrissie
authors.initials: C
authors.lastname: Segal
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: Erik O
authors.initials: EO
authors.lastname: Solberg
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: Jenny
authors.initials: J
authors.lastname: Tobin
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Zimmer
authors.affiliation: Ironwood Pharmaceuticals, Inc. 301 Binney Street Cambridge, Massachusetts 02142 United States.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Currie
keywords: IWP-051; NO-independent stimulators; Soluble guanylate cyclase; heme-dependent sGC stimulators; nitric oxide; sGC