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Design of Selective sPLA2-X Inhibitor (-)-2-{2-[Carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl]pyridine-2-yl}propanoic Acid.
Giordanetto, Fabrizio; Knerr, Laurent; Nordberg, Peter; Pettersen, Daniel; Selmi, Nidhal; Beisel, Hans-Georg; de la Motte, Hannah; Månsson, Åsa; Dahlström, Mikael; Broddefalk, Johan; Saarinen, Gabrielle; Klingegård, Fredrik; Hurt-Camejo, Eva; Rosengren, Birgitta; Wikström, Johannes; Wågberg, Maria; Brengdahl, Johan; Rohman, Mattias; Sandmark, Jenny; Åkerud, Tomas; Roth, Robert G; Jansen, Frank; Ahlqvist, Marie.
Afiliación
  • Giordanetto F; Medicinal Chemistry, Translational Sciences, Bioscience, and Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Knerr L; Medicinal Chemistry, Translational Sciences, Bioscience, and Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Nordberg P; Medicinal Chemistry, Translational Sciences, Bioscience, and Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Pettersen D; Medicinal Chemistry, Translational Sciences, Bioscience, and Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Selmi N; Medicinal Chemistry, Translational Sciences, Bioscience, and Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Beisel HG; Medicinal Chemistry, Translational Sciences, Bioscience, and Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • de la Motte H; Medicinal Chemistry, Translational Sciences, Bioscience, and Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Månsson Å; Medicinal Chemistry, Translational Sciences, Bioscience, and Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Dahlström M; Medicinal Chemistry, Translational Sciences, Bioscience, and Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Broddefalk J; Medicinal Chemistry, Translational Sciences, Bioscience, and Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Saarinen G; Medicinal Chemistry, Translational Sciences, Bioscience, and Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Klingegård F; Medicinal Chemistry, Translational Sciences, Bioscience, and Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Hurt-Camejo E; Medicinal Chemistry, Translational Sciences, Bioscience, and Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Rosengren B; Medicinal Chemistry, Translational Sciences, Bioscience, and Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Wikström J; Medicinal Chemistry, Translational Sciences, Bioscience, and Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Wågberg M; Medicinal Chemistry, Translational Sciences, Bioscience, and Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Brengdahl J; Reagents and Assay Development, Mechanistic Biology and Profiling, and Structure and Biophysics, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Rohman M; Reagents and Assay Development, Mechanistic Biology and Profiling, and Structure and Biophysics, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Sandmark J; Reagents and Assay Development, Mechanistic Biology and Profiling, and Structure and Biophysics, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Åkerud T; Reagents and Assay Development, Mechanistic Biology and Profiling, and Structure and Biophysics, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Roth RG; Reagents and Assay Development, Mechanistic Biology and Profiling, and Structure and Biophysics, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Jansen F; Reagents and Assay Development, Mechanistic Biology and Profiling, and Structure and Biophysics, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
  • Ahlqvist M; Medicinal Chemistry, Translational Sciences, Bioscience, and Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 89, Sweden.
ACS Med Chem Lett ; 9(7): 600-605, 2018 Jul 12.
Article en En | MEDLINE | ID: mdl-30034586
ABSTRACT
A lead generation campaign identified indole-based sPLA2-X inhibitors with a promising selectivity profile against other sPLA2 isoforms. Further optimization of sPLA2 selectivity and metabolic stability resulted in the design of (-)-17, a novel, potent, and selective sPLA2-X inhibitor with an exquisite pharmacokinetic profile characterized by high absorption and low clearance, and low toxicological risk. Compound (-)-17 was tested in an ApoE-/- murine model of atherosclerosis to evaluate the effect of reversible, pharmacological sPLA2-X inhibition on atherosclerosis development. Despite being well tolerated and achieving adequate systemic exposure of mechanistic relevance, (-)-17 did not significantly affect circulating lipid and lipoprotein biomarkers and had no effect on coronary function or histological markers of atherosclerosis.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2018 Tipo del documento: Article País de afiliación: Suecia
Texto completo
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2018 Tipo del documento: Article País de afiliación: Suecia