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Nitric Oxide. 2018 Aug 1;78:72-80. doi: 10.1016/j.niox.2018.05.009. Epub 2018 May 31.

Discovery and development of next generation sGC stimulators with diverse multidimensional pharmacology and broad therapeutic potential.

Author information

1
Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA. Electronic address: ebuys@ironwoodpharma.com.
2
Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA.

Abstract

Nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC), an enzyme that catalyzes the conversion of guanosine-5'-triphosphate (GTP) to cyclic guanosine-3',5'-monophophate (cGMP), transduces many of the physiological effects of the gasotransmitter NO. Upon binding of NO to the prosthetic heme group of sGC, a conformational change occurs, resulting in enzymatic activation and increased production of cGMP. cGMP modulates several downstream cellular and physiological responses, including but not limited to vasodilation. Impairment of this signaling system and altered NO-cGMP homeostasis have been implicated in cardiovascular, pulmonary, renal, gastrointestinal, central nervous system, and hepatic pathologies. sGC stimulators, small molecule drugs that synergistically increase sGC enzyme activity with NO, have shown great potential to treat a variety of diseases via modulation of NO-sGC-cGMP signaling. Here, we give an overview of novel, orally available sGC stimulators that Ironwood Pharmaceuticals is developing. We outline the non-clinical and clinical studies, highlighting pharmacological and pharmacokinetic (PK) profiles, including pharmacodynamic (PD) effects, and efficacy in a variety of disease models.

KEYWORDS:

Drug development; Fibrosis; Guanylyl cyclase; IWP-051; Inflammation; Metabolism; Multidimensional pharmacology; Neuronal function; Nitric oxide; Olinciguat; Praliciguat; Smooth muscle function; Stimulator; Vascular function

PMID:
29859918
DOI:
10.1016/j.niox.2018.05.009
[Indexed for MEDLINE]
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