(-)-SCH 57939: Synthesis and pharmacological properties of a potent, metabolically stable cholesterol absorption inhibitor

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 17, 1996, Pages 2069-2072

  Kirkup, Michael P ^a   Rizvi, Razia ^a   Shankar, Bandarpalle B ^a   Dugar, Sundeep ^a   Clader, John W ^a   McCombie, Stuart W ^a   Lin, Sue Ing ^a   Yumibe, Nathan ^a   Huie, Keith ^a   Van Heek, Margaret ^a   Compton, Douglas S ^a   Davis Jr , Harry R ^a   McPhail, Andrew T ^b  

^a MERCK RESEARCH LABORATORIES   (United States)

^b DUKE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,4 BIS(4 METHOXYPHENYL) 3 (3 PHENYLPROPYL) 2 AZETIDINONE; 2 AZETIDINONE DERIVATIVE; ANTILIPEMIC AGENT; LIVER ENZYME; SCH 57939; UNCLASSIFIED DRUG;

ANIMAL MODEL; ARTICLE; CHIRALITY; CHOLESTEROL BLOOD LEVEL; CONTROLLED STUDY; DRUG DESIGN; DRUG STABILITY; DRUG SYNTHESIS; HAMSTER; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; MONKEY; NONHUMAN; ORAL DRUG ADMINISTRATION; QUANTITATIVE STRUCTURE ACTIVITY RELATION; RAT; STEREOCHEMISTRY;

EID: 0030567853     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(96)00365-4     Document Type: Article

References (15)

1. Burnett, D. A.; Caplen, M. A.; Davis, H. R. Jr.; Burrier, R. E.; Clader, L. W. J. Med. Chem. 1994, 37, 1733.
2. For methods used in these studies see Salisbury, B. G.; Davis, H. R.; Burrier, R. E., Burnett, D. A.; Boykow, G.; Caplen, M. A.; Clemmons, A. L.; Compton, D. S.; Hoos, L. M.; McGregor, D. G.; Schnitzer-Polokoff, R.; Smith, A. A.; Weig, B. C.; Zilli, D. L.; Clader, J. W; Sybertz, E. J., Atherosclerosis 1995, 115, 45-63.
3. Dugar, S.; Yumibe, N.; Clader, J. W.; Vizziano, M.; Huie, K.; Van Heek, M.; Compton, D. S.; Davis, H. R.; Bioorg. and Med. Chem. Lett., (in press).
4. McKittrick. B.; Ma, K.; Dugar, S.; Clader, J. W.; Davis, H. R.; Czarniecki, M.; Bioorg. and Med. Chem. Lett., (submitted).
5. Davis, H. R.; Watkins, R. W.; Salisbury, B. G.; Compton, D. S.; Sybertz, E. J. and Burrier, R. E., Atherosclerosis, 1994, 109, 162.
6. Clader, J. W.; Burnett, D. A.; Caplen, M. A.; Domalski, M. S.; Dugar, S.; Vaccaro, W.; Sher, R.; Browne, M. E.; Zhao, H.; Burrier, R. E.; Salisbury, B. and Davis, H. R., manuscript in preparation.
7. For additional details of the asymmetric synthesis see: Shankar, B. B.; Kirkup, M. P.; McCombie, S. W.; Clader, J. W. and Ganguly, A. K., Tetrahedron Lett., in press.
8. 25D -41.4°, mp = 171-172°C).
9. Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K., and Moriwake, T., Tetrahedron, 1992, 48, 4067.
10. For a general procedure for reacting ethylzincoxylithium enolates with imines see Oguni, N.; and Ohkawa, Y., J. Chem. Soc., Chem. Commun., 1988, 1376.
11. Measured as percent reduction in liver cholesterol ester levels (L/CE) verses controls in the 7-day cholesterol-fed hamster model. Drug was administered by oral gavage as a corn oil suspension (See ref 2 for details). All compounds with indicated percent reductions were statistically different from the cholesterol-fed control group. The liver cholesterylester level for the 0.5% cholesterol fed controls was 22.14 mg ± 1.53 mg CE/g wet liver. The typical chow fed control is 1.0 mg CE/g wet liver. The compounds were evaluated in a series of separate seven day cholesterol-fed hamster studies, hence, direct comparisons among compounds were not performed.
12. 3) coupling constants for C4-H (δ 5.8, J=6 Hz) and inferred by literature precedent (see ref. 9).
13. b. The cis-(1'R) alcohol was not prepared in the p-fluorophenoxy series as SAR data for the corresponding alcohols in the carba series indicated that 1'R stereochemistry results in reduced activity.
14. A dose equimolar to 500 mpk of (-) SCH 48461 suspended in corn oil, was administered orally to female rats (n = 4) over 8 days. Plasma and enzyme induction analyses were conducted 2 h following the last dose. Blood samples were also collected at 2, 6 and 24 h to assess compound absorption/exposure. Plasma was analyzed using a validated HPLC assay, but drug levels were below the lower limit of quantitation (30-ng/ml).
15. A small but statistically significant increase in microsomal protein content per gram (17.8%, p < 0.01) and per total liver (20.8%, p < 0.05) relative to control animals was observed. All other enzyme induction parameters (i.e., cytochrome P-450 content, benzphetamine N-demethylase, 7-pentoxyresorufin O-dealkylase and 7-ethoxyresorufinase O- deethylase activity) were unaltered.