Literature DB >> 27190594

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

Takashi Nakai1, Nicholas R Perl1, Timothy C Barden1, Andrew Carvalho1, Angelika Fretzen1, Peter Germano1, G-Yoon J Im1, Hong Jin1, Charles Kim1, Thomas W-H Lee1, Kimberly Long1, Joel Moore1, Jason M Rohde1, Renee Sarno1, Chrissie Segal1, Erik O Solberg1, Jenny Tobin1, Daniel P Zimmer1, Mark G Currie1.   

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.

Entities:  

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

Year:  2016        PMID： 27190594      PMCID： PMC4867485          DOI： 10.1021/acsmedchemlett.5b00479

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  15 in total

1.  Metabolites of orally active NO-independent pyrazolopyridine stimulators of soluble guanylate cyclase.

Authors:  Alexander Straub; Jordi Benet-Buckholz; Rita Fröde; Armin Kern; Christian Kohlsdorfer; Peter Schmitt; Thomas Schwarz; Hans Martin Siefert; Johannes Peter Stasch
Journal:  Bioorg Med Chem       Date:  2002-06       Impact factor: 3.641

2.  A Unique Role of NO in the Control of Blood Flow.

Authors:  Ulrich Pohl; Cor de Wit
Journal:  News Physiol Sci       Date:  1999-04

3.  Antiinflammatory activity of soluble guanylate cyclase: cGMP-dependent down-regulation of P-selectin expression and leukocyte recruitment.

Authors:  Amrita Ahluwalia; Paul Foster; Ramona S Scotland; Peter G McLean; Anthony Mathur; Mauro Perretti; Salvador Moncada; Adrian J Hobbs
Journal:  Proc Natl Acad Sci U S A       Date:  2004-01-23       Impact factor: 11.205

Review 4.  NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential.

Authors:  Oleg V Evgenov; Pál Pacher; Peter M Schmidt; György Haskó; Harald H H W Schmidt; Johannes-Peter Stasch
Journal:  Nat Rev Drug Discov       Date:  2006-09       Impact factor: 84.694

Review 5.  Interspecies scaling: predicting clearance of drugs in humans. Three different approaches.

Authors:  I Mahmood; J D Balian
Journal:  Xenobiotica       Date:  1996-09       Impact factor: 1.908

6.  Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFβ signalling.

Authors:  Christian Beyer; Christoph Zenzmaier; Katrin Palumbo-Zerr; Rossella Mancuso; Alfiya Distler; Clara Dees; Pawel Zerr; Jingang Huang; Christiane Maier; Milena L Pachowsky; Andreas Friebe; Peter Sandner; Oliver Distler; Georg Schett; Peter Berger; Jörg H W Distler
Journal:  Ann Rheum Dis       Date:  2014-02-23       Impact factor: 19.103

7.  Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.

Authors:  L J Ignarro; G M Buga; K S Wood; R E Byrns; G Chaudhuri
Journal:  Proc Natl Acad Sci U S A       Date:  1987-12       Impact factor: 11.205

8.  Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin.

Authors:  Yifeng Li; Dandan Zhang; Wei Jin; Chunhong Shao; Pengrong Yan; Congjian Xu; Haihui Sheng; Yan Liu; Jinde Yu; Yuying Xie; Yingnan Zhao; Daru Lu; Daniel W Nebert; Donald C Harrison; Wei Huang; Li Jin
Journal:  J Clin Invest       Date:  2006-01-26       Impact factor: 14.808

9.  Riociguat: first global approval.

Authors:  Daniel Conole; Lesley J Scott
Journal:  Drugs       Date:  2013-11       Impact factor: 9.546

10.  Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension.

Authors:  Joachim Mittendorf; Stefan Weigand; Cristina Alonso-Alija; Erwin Bischoff; Achim Feurer; Michael Gerisch; Armin Kern; Andreas Knorr; Dieter Lang; Klaus Muenter; Martin Radtke; Hartmut Schirok; Karl-Heinz Schlemmer; Elke Stahl; Alexander Straub; Frank Wunder; Johannes-Peter Stasch
Journal:  ChemMedChem       Date:  2009-05       Impact factor: 3.466
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  11 in total

1.  Synthesis and antimicrobial studies of novel derivatives of 4-(4-formyl-3-phenyl-1H-pyrazol-1-yl)benzoic acid as potent anti-Acinetobacter baumannii agents.

Authors:  Devin Allison; Evan Delancey; Hunter Ramey; Conrad Williams; Zakeyah Ali Alsharif; Hessa Al-Khattabi; Allyn Ontko; David Gilmore; Mohammad A Alam
Journal:  Bioorg Med Chem Lett       Date:  2016-12-29       Impact factor: 2.823

Review 2.  Redox regulation of soluble guanylyl cyclase.

Authors:  Rohan C Shah; Subramaniam Sanker; Katherine C Wood; Brittany G Durgin; Adam C Straub
Journal:  Nitric Oxide       Date:  2018-03-22       Impact factor: 4.427

3.  Discovery of stimulator binding to a conserved pocket in the heme domain of soluble guanylyl cyclase.

Authors:  Jessica A Wales; Cheng-Yu Chen; Linda Breci; Andrzej Weichsel; Sylvie G Bernier; James E Sheppeck; Robert Solinga; Takashi Nakai; Paul A Renhowe; Joon Jung; William R Montfort
Journal:  J Biol Chem       Date:  2017-12-08       Impact factor: 5.157

Review 4.  AMPK and the Challenge of Treating Hypoxic Pulmonary Hypertension.

Authors:  Karen Flores; Patricia Siques; Julio Brito; Silvia M Arribas
Journal:  Int J Mol Sci       Date:  2022-06-01       Impact factor: 6.208

5.  Soluble Guanylate Cyclase Stimulators and Activators.

Authors:  Peter Sandner; Daniel P Zimmer; G Todd Milne; Markus Follmann; Adrian Hobbs; Johannes-Peter Stasch
Journal:  Handb Exp Pharmacol       Date:  2021

6.  New pyridine and chromene scaffolds as potent vasorelaxant and anticancer agents.

Authors:  Dina H Dawood; Aladdin M Srour; Dalia O Saleh; Kelley J Huff; Francesca Greco; Helen M I Osborn
Journal:  RSC Adv       Date:  2021-09-02       Impact factor: 3.361

7.  Solution structures of the Shewanella woodyi H-NOX protein in the presence and absence of soluble guanylyl cyclase stimulator IWP-051.

Authors:  Cheng-Yu Chen; Woonghee Lee; Paul A Renhowe; Joon Jung; William R Montfort
Journal:  Protein Sci       Date:  2020-12-10       Impact factor: 6.993

8.  Olinciguat, an Oral sGC Stimulator, Exhibits Diverse Pharmacology Across Preclinical Models of Cardiovascular, Metabolic, Renal, and Inflammatory Disease.

Authors:  Daniel P Zimmer; Courtney M Shea; Jenny V Tobin; Boris Tchernychev; Peter Germano; Kristie Sykes; Ali R Banijamali; Sarah Jacobson; Sylvie G Bernier; Renee Sarno; Andrew Carvalho; Yueh-Tyng Chien; Regina Graul; Emmanuel S Buys; Juli E Jones; James D Wakefield; Gavrielle M Price; Jennifer G Chickering; G Todd Milne; Mark G Currie; Jaime L Masferrer
Journal:  Front Pharmacol       Date:  2020-04-08       Impact factor: 5.810

9.  cGMP Imaging in Brain Slices Reveals Brain Region-Specific Activity of NO-Sensitive Guanylyl Cyclases (NO-GCs) and NO-GC Stimulators.

Authors:  Stefanie Peters; Michael Paolillo; Evanthia Mergia; Doris Koesling; Lea Kennel; Achim Schmidtko; Michael Russwurm; Robert Feil
Journal:  Int J Mol Sci       Date:  2018-08-07       Impact factor: 5.923

Review 10.  Structural Perspectives on the Mechanism of Soluble Guanylate Cyclase Activation.

Authors:  Elizabeth C Wittenborn; Michael A Marletta
Journal:  Int J Mol Sci       Date:  2021-05-21       Impact factor: 5.923
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