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BMC Pharmacology and Toxicology

Open Access

Discovery of IWP-051, a Novel Orally Bioavailable Soluble Guanylate Cyclase Stimulator with Sustained and Dose-Dependent Hemodynamic Effects

  • Takashi Nakai1,
  • Nicholas R Perl1,
  • Rajesh R Iyengar1Email author,
  • Ara Mermerian1,
  • G-Yoon J Im1,
  • Thomas W-H Lee1,
  • Glen R Rennie1,
  • James Jia1,
  • Paul A Renhowe1,
  • Timothy C Barden1,
  • James E SheppeckII1,
  • Karthik Iyer1,
  • Joon Jung1,
  • G Todd Milne1,
  • Chrissie Segal1,
  • Kimberly Long1,
  • Joy Miyashiro1,
  • Sylvie Bernier1,
  • Sarah Jacobson1,
  • Jenny Tobin1,
  • Courtney Shea1,
  • Peter Germano1,
  • Yueh-tyng Chien1 and
  • Daniel Zimmer1
BMC Pharmacology and Toxicology201516(Suppl 1):A59

https://doi.org/10.1186/2050-6511-16-S1-A59

Published: 2 September 2015

Background

Soluble guanylate cyclase (sGC) stimulators are small molecule agonists of sGC that are heme-dependent, nitric oxide (NO)-independent, and act in synergy with NO. Herein, we describe a novel class of pyrazole-pyrimidine sGC stimulators and their evolution from an early lead to IWP-051 by optimizing SAR for in vitro potency, pharmacokinetic parameters, and off-target activity.

Conclusion

IWP-051 is a potent sGC stimulator with >99% plasma protein binding, high metabolic stability, high permeability, and no efflux in a Caco-2 model of intestinal absorption. In rat PK studies, IWP-051 had low clearance and a low volume of distribution. Its elimination half-life in rats was >4 hrs. IWP-051 exhibited dose-related oral exposure, its Tmax was >3 hrs in rats, and its oral bioavailability was >40% in mice, rats, and dogs. In normotensive rats, oral doses of IWP-051 ranging from 1 to 100 mg/kg decreased mean arterial pressure in a sustained and dose-responsive manner. Distinct features of the pharmacologic profile of IWP-051, including metabolic stability, protracted gastrointestinal absorption, and sustained effect on hemodynamics upon oral dosing in rats, make IWP-051 an exciting pharmacologic advancement in the sGC stimulator class.

Fig 1

Authors’ Affiliations

(1)
Ironwood Pharmaceuticals Inc.

Copyright

© Nakai et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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