Metabolism and structure activity data based drug design: Discovery of (-) SCH 53079 an analog of the potent cholesterol absorption inhibitor (-) SCH 48461

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 11, 1996, Pages 1271-1274

  Dugar, Sundeep ^a   Yumibe, Nathan ^a   Clader, John W ^a   Vizziano, Monica ^a   Huie, Keith ^a   Van Heek, Margaret ^a   Compton, Douglas S ^a   Davis Jr , Harry R ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CRICETINAE; MACACA MULATTA;

1,4 BIS(4 METHOXYPHENYL) 3 (3 PHENYLPROPYL) 2 AZETIDINONE; 3 [2 (4 FLUOROPHENOXY)ETHYL] 4 (4 METHOXYPHENYL) 1 PHENYL 2 AZETIDINONE; ANTILIPEMIC AGENT; SCH 53079; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CHOLESTEROL METABOLISM; DRUG CONFORMATION; DRUG DESIGN; DRUG HYDROXYLATION; DRUG POTENCY; DRUG SYNTHESIS; HAMSTER; NONHUMAN; RHESUS MONKEY; STRUCTURE ACTIVITY RELATION;

EID: 0029975253     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(96)00214-4     Document Type: Article

References (10)

1. Burnett, D.; Caplen, M.; Davis, H. Jr.; Burrier, R.; Clader, J. J. Med. Chem. 1994, 37, 1733.
2. Salisbury, B.; Davis, H.; Burrier, R., Burnett, D.; Boykow, G.; Caplen, M.; Clemmons, A.; Compton, D.; Hoos, L.; McGregor, D.; Schnitzer-Polokoff, R.; Smith, A.; Weig, B.; Zilli, D.; Clader, J.; Sybertz, E. Atherosclerosis 1995, 115, 45.
3. Schintzer-Polokoff, R.; Compton, D.; Boykow, G.; Davis, H.; Burrier, R. Comp. Biochem. Physiol. 1991, 197, 304.
4. Davis, H.; Watkins, R.; Salisbury, B.; Compton, D.; Sybertz, E.; Burrier, R. Atherosclerosis, 1994, 109, 162.
5. Metabolism studies were carried out in male rats, beagle dogs and cynomolgus monkeys using a single (gavage) oral dose of 50mpk. Bile was collected and part of it was treated with Glusulase®. Both pre-and post-Glusulase® portions were analyzed by HPLC. Individual metabolites were identified by coinjection with authentic samples and confirmed by LC/MS.
6. Clader, J.; Burnett, D.; Caplen, M.; Domalski, M.; Dugar, S.; Vaccaro, W.; Sher, R.; Browne, M.; Zhao, H.; Burrier, R.; Salisbury, B.; Davis, H. Jr. 2-Azetidinone Cholesterol Absorption Inhibitors: Structure-Activity Relationships on the Heterocyclic Nucleus, manuscript in preparation
7. Measured by reduction in liver cholesterol ester levels (L/CE) in the seven-day cholesterol-fed hamster model, see reference 1. All compounds with indicated percent reductions were statistically different from the cholesterol-fed control group. The compounds were evaluated in a series of separate seven-day cholesterol-fed hamster studies hence, direct statistical comparisons among the compounds were not performed.
8. The enantiomers were separated on a Chiralcel OD column (90% hexane/10% 2-propanol).
9. A bile duct-cannulated rat, beagle dog and cynamolgus monkey were each orally administered a single gavage dose of 50 mpk (-) 4 and bile was collected over a 0-24 h period. Bile samples were treated with Glusulase® and both treated and untreated samples were analyzed using a HPLC system with a Hypersil ODS analytical column (4.6 × 250 mm, 5mm) with UV detection at 260 nm. The peaks were isolated using a preparative HPLC system and analyzed by mass spectrometry.
10. Female rats received a single oral (gavage) dose of 487 mg (-)5/kg in corn oil. Plasma levels of parent drug in hamsters or monkeys was not determined.