2-Hydroxy-N-arylbenzenesulfonamides as ATP-citrate lyase inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 11, 2007, Pages 3208-3211

  Li, James J ^a   Wang, Haixia ^a   Tino, Joseph A ^a   Robl, Jeffrey A ^a   Herpin, Timothy F ^a   Lawrence, R Michael ^a   Biller, Scott ^a   Jamil, Haris ^a   Ponticiello, Randy ^a   Chen, Luping ^a   Chu, Ching hsuen ^a   Flynn, Neil ^a   Cheng, Dong ^a   Zhao, Rulin ^a   Chen, Bangchi ^a   Schnur, Dora ^a   Obermeier, Mary T ^a   Sasseville, Vito ^a   Padmanabha, Ramesh ^a   Pike, Kristen ^a   Harrity, Thomas ^a   more..

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

ATP citrate lyase (ACL) inhibitors; Glycemic profiles and weight loss; Lipid

Indexed keywords

2 HYDROXY N ARYLBENZENESULFONAMIDE DERIVATIVE; ADENOSINE TRIPHOSPHATE CITRATE LYASE; CHOLESTEROL; ENZYME INHIBITOR; GLUCOSE; SULFONAMIDE; TRIACYLGLYCEROL; UNCLASSIFIED DRUG;

ARTICLE; CELL MEMBRANE PERMEABILITY; CONTROLLED STUDY; DRUG ACTIVITY; DRUG IDENTIFICATION; DRUG INHIBITION; DRUG POTENCY; DRUG STRUCTURE; HUMAN; HUMAN CELL; IC 50; IN VITRO STUDY; LIPID DIET; NONHUMAN; WEIGHT GAIN;

ADIPOSE TISSUE; ANIMALS; ANTI-OBESITY AGENTS; ATP CITRATE (PRO-S)-LYASE; BENZENE; BLOOD GLUCOSE; BODY WEIGHT; CELLS, CULTURED; CHOLESTEROL; ENZYME INHIBITORS; MICE; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; TRIGLYCERIDES;

MUS;

EID: 34247866501     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.03.017     Document Type: Article

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16. The in vitro enzyme assay was performed using recombinant human ACL, as described in Ref. 11.
17. General synthetic scheme for the preparation of 2-hydroxy-N-phenylbenzenesulfonamides 4-14 is described herein.{A figure is presented}
18. 4S: Calcd C, 53.78; H, 3.56; N, 3.30; S, 7.55; Cl, 16.71. Found: C, 53.63; H, 3.57; N, 3.17; S, 7.86; Cl, 16.62.
19. 14C]-labeled in the total lipids was measured using Packard Imager.
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21. max = 0.5 h (po), total body clearance 17.3 mL/min/kg.
22. Eight-week-old C57BL/6 mice with an average 30 g of body weight were used with five mice per group. The high-fat diet contained 30% coconut oil and 45% sucrose, whereas the normal-diet group was fed with Teklad Global 18% protein rodent diet. The average food consumption for the high-fat control and 9 treated group was 3.2 ± 0.2 g/day/mouse. The average food consumption for normal diet mice was 4.0 ± 0.1 g/day/mouse.
23. 50 of 6 μM and 12 μM against human ACC1 and ACC2, respectively. While it is unlikely that the in vivo efficacy of 9 in the high-fat feeding model was the result of ACC inhibition, contribution of this mechanism or other potential off-target mechanisms in the pharmacological response cannot be completely ruled out.