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Soluble guanylate cyclase stimulators for the treatment of hypertension: Discovery of MK-2947.
Brockunier, Linda; Stelmach, John; Guo, Jian; Spencer, Tracy; Rosauer, Keith; Bansal, Alka; Cai, Sheng-Jian; Chen, Nancy; Cummings, John; Huang, Li; Johnson, Timothy; Levesque, Sonia; Luo, Lin; Maloney, Kevin; Metzger, Joseph; Mortko, Christopher; Ortega, Karen; Pai, Lee-Yuh; Pereira, Antonio; Salituro, Gino; Shang, Jackie; Shepherd, Cherrie; Sherrie Xu, Shiyao; Yang, Qifeng; Cui, Jisong; Roy, Sophie; Parmee, Emma; Raghavan, Subharekha.
Affiliation
  • Brockunier L; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Stelmach J; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Guo J; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Spencer T; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Rosauer K; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Bansal A; Cardio-metabolic Disease, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Cai SJ; Cardio-metabolic Disease, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Chen N; In vivo pharmacology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Cummings J; Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Huang L; Cardio-metabolic Disease, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Johnson T; Investigative In-Vivo Safety Pharmacology, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
  • Levesque S; In vivo pharmacology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Luo L; Cardio-metabolic Disease, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Maloney K; Process Research & Development, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Metzger J; In vivo pharmacology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Mortko C; Discovery Pharmaceutical Science, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Ortega K; In vivo pharmacology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Pai LY; In vivo pharmacology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Pereira A; Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Salituro G; Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Shang J; Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Shepherd C; In vivo pharmacology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Sherrie Xu S; Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Yang Q; Cardio-metabolic Disease, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Cui J; Cardio-metabolic Disease, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Roy S; Cardio-metabolic Disease, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Parmee E; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • Raghavan S; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: subha_raghavan@merck.com.
Bioorg Med Chem Lett ; 30(21): 127574, 2020 11 01.
Article in En | MEDLINE | ID: mdl-32980512
ABSTRACT
The NO-sGC-cGMP signaling pathway plays an important role in the cardiovascular system. Loss of nitric oxide tone or impaired signaling has been associated with cardiovascular diseases, such as hypertension, pulmonary hypertension and heart failure. Direct activation of sGC enzyme independent of NO represents a novel approach for modulating NO signaling with tremendous therapeutic potential. Herein, we describe the design of a structurally novel class of heme-dependent sGC stimulators containing the 3,3-dimethylpyrrolidin-2-one moiety which resulted in the identification of the potent, selective stimulator 30 (MK-2947) for the treatment of hypertension.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Drug Discovery / Soluble Guanylyl Cyclase / Hypertension / Antihypertensive Agents Limits: Humans Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2020 Document type: Article Affiliation country:
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Drug Discovery / Soluble Guanylyl Cyclase / Hypertension / Antihypertensive Agents Limits: Humans Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2020 Document type: Article Affiliation country: