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

Autor: Buys ES; Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA. Electronic address: ebuys@ironwoodpharma.com., Zimmer DP; Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA., Chickering J; Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA., Graul R; Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA., Chien YT; Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA., Profy A; Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA., Hadcock JR; Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA., Masferrer JL; Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA., Milne GT; Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA.
Jazyk: angličtina
Zdroj: Nitric oxide : biology and chemistry [Nitric Oxide] 2018 Aug 01; Vol. 78, pp. 72-80. Date of Electronic Publication: 2018 May 31.
DOI: 10.1016/j.niox.2018.05.009
Abstrakt: 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.
(Copyright © 2018 Ironwood Pharmaceuticals Inc. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: