PMID- 29859918
OWN - NLM
STAT- MEDLINE
DCOM- 20190903
LR  - 20190903
IS  - 1089-8611 (Electronic)
IS  - 1089-8603 (Linking)
VI  - 78
DP  - 2018 Aug 1
TI  - Discovery and development of next generation sGC stimulators with diverse 
      multidimensional pharmacology and broad therapeutic potential.
PG  - 72-80
LID - S1089-8603(18)30071-5 [pii]
LID - 10.1016/j.niox.2018.05.009 [doi]
AB  - 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.
CI  - Copyright (c) 2018 Ironwood Pharmaceuticals Inc. Published by Elsevier Inc. All 
      rights reserved.
FAU - Buys, E S
AU  - Buys ES
AD  - Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA. Electronic 
      address: ebuys@ironwoodpharma.com.
FAU - Zimmer, D P
AU  - Zimmer DP
AD  - Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA.
FAU - Chickering, J
AU  - Chickering J
AD  - Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA.
FAU - Graul, R
AU  - Graul R
AD  - Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA.
FAU - Chien, Y T
AU  - Chien YT
AD  - Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA.
FAU - Profy, A
AU  - Profy A
AD  - Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA.
FAU - Hadcock, J R
AU  - Hadcock JR
AD  - Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA.
FAU - Masferrer, J L
AU  - Masferrer JL
AD  - Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA.
FAU - Milne, G T
AU  - Milne GT
AD  - Ironwood Pharmaceuticals Inc., 301 Binney St, Cambridge, MA, USA.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20180531
PL  - United States
TA  - Nitric Oxide
JT  - Nitric oxide : biology and chemistry
JID - 9709307
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Enzyme Activators)
RN  - EC 4.6.1.2 (Soluble Guanylyl Cyclase)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - Anti-Inflammatory Agents/administration & 
      dosage/pharmacokinetics/pharmacology/therapeutic use
MH  - Clinical Trials as Topic
MH  - Drug Discovery
MH  - Enzyme Activation/drug effects
MH  - Enzyme Activators/administration & 
      dosage/pharmacokinetics/pharmacology/*therapeutic use
MH  - Fibrosis/drug therapy
MH  - Humans
MH  - Signal Transduction/drug effects
MH  - Soluble Guanylyl Cyclase/*metabolism
OTO - NOTNLM
OT  - Drug development
OT  - Fibrosis
OT  - Guanylyl cyclase
OT  - IWP-051
OT  - Inflammation
OT  - Metabolism
OT  - Multidimensional pharmacology
OT  - Neuronal function
OT  - Nitric oxide
OT  - Olinciguat
OT  - Praliciguat
OT  - Smooth muscle function
OT  - Stimulator
OT  - Vascular function
EDAT- 2018/06/04 06:00
MHDA- 2019/09/04 06:00
CRDT- 2018/06/04 06:00
PHST- 2018/03/08 00:00 [received]
PHST- 2018/05/29 00:00 [revised]
PHST- 2018/05/30 00:00 [accepted]
PHST- 2018/06/04 06:00 [pubmed]
PHST- 2019/09/04 06:00 [medline]
PHST- 2018/06/04 06:00 [entrez]
AID - S1089-8603(18)30071-5 [pii]
AID - 10.1016/j.niox.2018.05.009 [doi]
PST - ppublish
SO  - Nitric Oxide. 2018 Aug 1;78:72-80. doi: 10.1016/j.niox.2018.05.009. Epub 2018 May 
      31.