Discovery of a potent sGC stimulator with once-daily dosing potential for the treatment of hypertension

  • Bioorg Med Chem Lett. 2026 Nov:140:130724. doi: 10.1016/j.bmcl.2026.130724.
Subharekha Raghavan  1 ,  Linda Brockunier  2 ,  Jian Guo  2 ,  Keith Rosauer  2 ,  Cameron Smith  2 ,  Qifeng Yang  3 ,  Cherrie Shepherd  4 ,  Liming Yang  4 ,  Lee-Yuh Pai  4 ,  Joseph Metzger  4 ,  Antonio Pereira  5 ,  Gino Salituro  5 ,  Shiyao Sherrie Xu  5 ,  Timothy Johnson  6 ,  Kevin Maloney  7 ,  Christopher Mortko  8 ,  Sophie Roy  3 ,  Emma Parmee  2
Affiliations
  • 1. Discovery Chemistry, Merck & Co., Inc., 121E Lincoln Av, Rahway, NJ, 07065, USA. Electronic address: [email protected].
  • 2. Discovery Chemistry, Merck & Co., Inc., 121E Lincoln Av, Rahway, NJ, 07065, USA.
  • 3. Cardio-metabolic Disease, Merck & Co., Inc., 121E Lincoln Av, Rahway, NJ, 07065, USA.
  • 4. In vivo pharmacology, Merck & Co., Inc., 121E Lincoln Av, Rahway, NJ, 07065, USA.
  • 5. Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, 121E Lincoln Av, Rahway, New Jersey, 07065, USA.
  • 6. Investigative In-Vivo Safety Pharmacology, Merck & Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, USA.
  • 7. Process Research & Development, Merck & Co., Inc., 121E Lincoln Av, Rahway, NJ, 07065, USA.
  • 8. Discovery Pharmaceutical Science, Merck & Co., Inc., 121E Lincoln Av, Rahway, NJ, 07065, USA.
PMID: 42379529 DOI: 10.1016/j.bmcl.2026.130724
Abstract

Endothelial dysfunction and impaired NO-sGC - cGMP signaling in Hypertension drive the need for next-generation soluble Guanylate Cyclase (sGC) stimulators with improved pharmacokinetics and once-daily dosing potential. Metabolism-guided optimization of MK-2947, which showed robust preclinical blood pressure lowering but exhibited compound-specific toxicity and a projected human half-life of ∼12 h, led to the identification of compound 20, a potent sGC stimulator (EC₅₀ = 44 nM) with improved pharmacokinetics and sustained blood pressure lowering in preclinical models (≥24 h). Preclinical PK/PD data support compound 20 as a structurally differentiated sGC stimulator with a profile consistent with once-daily dosing potential, reflecting an improved balance of pharmacokinetic and pharmacodynamic properties, pending further safety evaluation.

Keywords
Blood pressure; Cyclic guanosine 3′,5′ monophosphate (cGMP); Hypertension; NO-sGC-cGMP signaling; Once-daily dosing; Soluble guanylate cyclase (sGC); Spontaneously hypertensive rats (SHRs); sGC stimulator.
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