Identification and Preliminary Characterization of a Potent, Safe, and Orally Efficacious Inhibitor of Acyl-CoA:Diacylglycerol Acyltransferase 1
A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound 14. Oral administration at doses ≥0.03 mg/kg significantly reduced postprandial triglycerides in mice followin...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-02, Vol.55 (4), p.1751-1757 |
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| container_title | Journal of medicinal chemistry |
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| creator | Yeh, Vince S. C Beno, David W. A Brodjian, Sevan Brune, Michael E Cullen, Steven C Dayton, Brian D Dhaon, Madhup K Falls, Hugh D Gao, Ju Grihalde, Nelson Hajduk, Philip Hansen, T. Matthew Judd, Andrew S King, Andrew J Klix, Russel C Larson, Kelly J Lau, Yau Y Marsh, Kennan C Mittelstadt, Scott W Plata, Dan Rozema, Michael J Segreti, Jason A Stoner, Eric J Voorbach, Martin J Wang, Xiaojun Xin, Xili Zhao, Gang Collins, Christine A Cox, Bryan F Reilly, Regina M Kym, Philip R Souers, Andrew J |
| description | A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound 14. Oral administration at doses ≥0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology and toxicology studies demonstrated a clean profile up to high plasma levels, thus culminating in the nomination of 14 as clinical candidate ABT-046. |
| doi_str_mv | 10.1021/jm201524g |
| format | Article |
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C ; Beno, David W. A ; Brodjian, Sevan ; Brune, Michael E ; Cullen, Steven C ; Dayton, Brian D ; Dhaon, Madhup K ; Falls, Hugh D ; Gao, Ju ; Grihalde, Nelson ; Hajduk, Philip ; Hansen, T. Matthew ; Judd, Andrew S ; King, Andrew J ; Klix, Russel C ; Larson, Kelly J ; Lau, Yau Y ; Marsh, Kennan C ; Mittelstadt, Scott W ; Plata, Dan ; Rozema, Michael J ; Segreti, Jason A ; Stoner, Eric J ; Voorbach, Martin J ; Wang, Xiaojun ; Xin, Xili ; Zhao, Gang ; Collins, Christine A ; Cox, Bryan F ; Reilly, Regina M ; Kym, Philip R ; Souers, Andrew J</creator><creatorcontrib>Yeh, Vince S. C ; Beno, David W. A ; Brodjian, Sevan ; Brune, Michael E ; Cullen, Steven C ; Dayton, Brian D ; Dhaon, Madhup K ; Falls, Hugh D ; Gao, Ju ; Grihalde, Nelson ; Hajduk, Philip ; Hansen, T. Matthew ; Judd, Andrew S ; King, Andrew J ; Klix, Russel C ; Larson, Kelly J ; Lau, Yau Y ; Marsh, Kennan C ; Mittelstadt, Scott W ; Plata, Dan ; Rozema, Michael J ; Segreti, Jason A ; Stoner, Eric J ; Voorbach, Martin J ; Wang, Xiaojun ; Xin, Xili ; Zhao, Gang ; Collins, Christine A ; Cox, Bryan F ; Reilly, Regina M ; Kym, Philip R ; Souers, Andrew J</creatorcontrib><description>A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound 14. Oral administration at doses ≥0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. 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| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2012-02, Vol.55 (4), p.1751-1757 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_crossref_primary_10_1021_jm201524g |
| source | MEDLINE; American Chemical Society Journals |
| subjects | Administration, Oral Animals Biological Availability Caco-2 Cells Databases, Factual Diacylglycerol O-Acyltransferase - antagonists & inhibitors Diacylglycerol O-Acyltransferase - chemistry Dogs Female Ferrets Gastrointestinal Transit - drug effects HeLa Cells Hemodynamics - drug effects Humans Hyperlipidemias - blood Hyperlipidemias - drug therapy Male Mice Mice, Inbred C57BL Microsomes, Liver - metabolism Postprandial Period Pyrazoles - chemical synthesis Pyrazoles - pharmacokinetics Pyrazoles - pharmacology Pyrimidines - chemical synthesis Pyrimidines - pharmacokinetics Pyrimidines - pharmacology Rats Recombinant Proteins - antagonists & inhibitors Recombinant Proteins - chemistry Structure-Activity Relationship Triglycerides - blood Vomiting - chemically induced |
| title | Identification and Preliminary Characterization of a Potent, Safe, and Orally Efficacious Inhibitor of Acyl-CoA:Diacylglycerol Acyltransferase 1 |
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