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Sulfonylated Benzothiazoles as Inhibitors of Endothelial Lipase.
Johnson, James A; Tora, George; Pi, Zulan; Phillips, Monique; Yin, Xiaohong; Yang, Richard; Zhao, Lei; Chen, Alice Y; Taylor, David S; Basso, Michael; Rose, Anne; Behnia, Kamelia; Onorato, Joelle; Chen, Xue-Qing; Abell, Lynn M; Lu, Hao; Locke, Gregory; Caporuscio, Christian; Galella, Michael; Adam, Leonard P; Gordon, David; Wexler, Ruth R; Finlay, Heather J.
Afiliación
  • Johnson JA; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Tora G; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Pi Z; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Phillips M; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Yin X; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Yang R; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Zhao L; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Chen AY; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Taylor DS; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Basso M; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Rose A; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Behnia K; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Onorato J; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Chen XQ; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Abell LM; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Lu H; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Locke G; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Caporuscio C; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Galella M; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Adam LP; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Gordon D; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Wexler RR; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Finlay HJ; Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
ACS Med Chem Lett ; 9(12): 1263-1268, 2018 Dec 13.
Article en En | MEDLINE | ID: mdl-30613337
ABSTRACT
Endothelial lipase (EL) selectively metabolizes high density lipoprotein (HDL) particles. Inhibition of EL has been shown to increase HDL concentration in preclinical animal models and was targeted as a potential treatment of atherosclerosis. We describe the introduction of an α-sulfone moiety to a benzothiazole series of EL inhibitors resulting in increased potency versus EL. Optimization for selectivity versus hepatic lipase and pharmacokinetic properties resulted in the discovery of 24, which showed good in vitro potency and bioavailability but, unexpectedly, did not increase HDL in the mouse pharmacodynamic model at the target plasma exposure.
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Texto completo: 1 Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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XML
PubMed Links
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Texto completo: 1 Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos