Skip to content

Advertisement

You're viewing the new version of our site. Please leave us feedback.

Learn more

BMC Pharmacology and Toxicology

Open Access

Concomitant administration of sGC stimulators with common classes of anti-hypertensive agents results in increased efficacy in spontaneously hypertensive rats

  • Peter Germano1Email author,
  • Jenny Tobin1,
  • Robert Jefferson1,
  • Courtney Shea1,
  • Adaline Smith1,
  • G-Yoon Jamie Im1,
  • James SheppeckII1,
  • James Wakefield1,
  • Kristie Sykes1,
  • Maria Ribadeneira1,
  • Samuel Rivers1 and
  • Jaime Masferrer1
BMC Pharmacology and Toxicology201516(Suppl 1):A54

https://doi.org/10.1186/2050-6511-16-S1-A54

Published: 2 September 2015

Background

Soluble guanylate cyclase (sGC) stimulators demonstrate smooth muscle relaxation and vasodilation via the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway. A novel class of sGC stimulators, the pyrazole-pyrimidines, was synthesized with the objective of creating a potent, once-a-day (QD) oral treatment for cardiovascular diseases. Several compounds from this class were identified as potent stimulators of sGC in vitro (EC50 = 40-287 nM). These compounds were evaluated in pharmacokinetic (PK) and blood pressure pharmacodynamics (PD) in vivo rat and dog models and were shown to exhibit sustained compound exposure (Thalf = >7 hours in preclinical species) after oral dosing, predicting QD dosing in humans. Further, they significantly decreased mean arterial blood pressure (MAP (≥ 10mmHg) after oral dosing. The potential for sGC stimulators to work in combination with reference antihypertensive therapies was assessed in an in vivo PD assay in a spontaneous hypertensive rat (SHR) model. Doses of losartan, atenolol, amlodipine, and our sGC stimulators that induced an effect (< 30mmHg) on MAP were chosen. IWP-121, a representative sGC stimulator, was shown to provide additional MAP lowering effects when combined with losartan, atenolol, or amlodipine, resulting in an increase in overall blood pressure effects between 5-50%. By linking compound concentration to blood pressure change for each compound alone and in combination, we were able to assess the PK/PD relationships for the individual and combined effects.

Conclusion

sGC stimulators from the pyrazole-pyrimidine class demonstrated potent effects in lowering blood pressure in rats and dogs with a PK profile consistent with predicted once a day dosing in humans. Furthermore, sGC stimulator(IWP-121) enhanced the blood pressure lowering effects of standard anti-hypertensive agents in the rat and may provide opportunities for treating patients with resistant hypertension.

Authors’ Affiliations

(1)
Ironwood Pharmaceuticals Inc.

Copyright

© Germano 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.

Advertisement