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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 de 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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Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Découverte de médicament / Soluble guanylyl cyclase / Hypertension artérielle / Antihypertenseurs Limites: Humans Langue: En Journal: Bioorg Med Chem Lett Sujet du journal: BIOQUIMICA / QUIMICA Année: 2020 Type de document: Article Pays d'affiliation: États-Unis d'Amérique
Texte intégral
Ajouter à My VHL
Imprimer
XML
PubMed Links
Recherche sur Google

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Découverte de médicament / Soluble guanylyl cyclase / Hypertension artérielle / Antihypertenseurs Limites: Humans Langue: En Journal: Bioorg Med Chem Lett Sujet du journal: BIOQUIMICA / QUIMICA Année: 2020 Type de document: Article Pays d'affiliation: États-Unis d'Amérique