Communications to the Editor
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14 2125
(6) Poulter, C. D.; Capson, T. L.; Thompson, M. D.; Bard, R. S.
Squalene synthase. Inhibition by ammonium analogues of
carbocationic intermediates in the conversion of presqualene
diphosphate to squalene. J . Am. Chem. Soc. 1989, 111, 3734-
3737.
(7) Baxter, A.; Fitzgerald, B. J .; Hutson, J . L.; McCarthy, A. D.;
Motteram, J . M.; Ross, B. C.; Sapra, M.; Snowden, M. A.; Watson,
N. S.; Williams, R. J .; Wrigt, C. Squalestatin 1, a potent inhibitor
of squalene synthase, which lowers serum cholesterol in vivo.
J . Biol. Chem. 1992, 267, 11705-11708.
(8) Bergstrom, J . D.; Kurtz, M. M.; Rew, D. J .; Amend, A. M.;
Karkas, J . D.; Bostedor, R. G.; Bansal, V. S.; Dufresne, C.;
VanMiddlesworth, F. L.; Hensens, O. D.; Liesch, J . M.; Zink, D.
L.; Wilson, K. E.; Onishi, J .; Milligan, J . A.; Bills, G.; Kaplan,
L.; Omstead, M. N.; J enkins, R. G.; Huang, L.; Meinz, M. S.;
Quinn, L.; Burg, R. W.; Kong, Y. L.; Mochales, S.; Mojena, M.;
Martin, I.; Pelaez, F.; Diez, M. T.; Alberts, A. W. Zaragozic
acids: a family of fungal metabolites. Proc. Natl. Acad. Sci.
U.S.A. 1993, 90, 80-84.
(9) For a recent review, see: Nadin, A.; Nicolaou, K. C. Chemistry
and biology of the zaragozic acids (squalestatins). Angew. Chem.,
Int. Ed. Engl. 1996, 35 (15), 1623-1656.
(10) Ponpipom, M. M.; Girotra, N. N.; Bugianesi, R. L.; Roberts, C.
D.; Berger, G. D.; Burk, R. M.; Marquis, R. W.; Parsons, W. H.;
Bartzal, K. F.; Bergstom, J . D.; Kurtz, M. M.; Onishi, J . C.; Rew,
D. J . Structure-activity relationships of C1 and C6 side chains
of zaragozic acid A derivatives. J . Med. Chem. 1994, 37, 4031-
4051.
(11) Dickson, J . K.; Biller, S. A.; Magnin, D. R.; Petrillo, E. W., J r.;
Hillyer, J . W.; Hsieh, D. C.; Lan, S. J .; Rienhart, J . K.; Gregg,
R. E.; Harrity, T. W.; J olibois, K. G.; Kalinowski, S. S.; Kunsel-
man, L. K.; Mookhtiar, K. A.; Ciosek, C. P., J r. Orally active
squalene synthase inhibitors: bis(acyloxy)alkyl) prodrugs of the
a-phosphonosulfonic acid moiety. J . Med. Chem. 1996, 39, 661-
664.
(12) Iwasawa, Y.; Shibata, J .; Mitsuya, M.; Masaki, H.; Hayashi, M.;
Kanno, T.; Sawasaki, Y.; Hisaka, A.; Kamei, T.; Tomimoto, K.
J -104,123, A novel and orally-active inhibitor of squalene syn-
thase: stereoselective synthesis and cholesterol lowering effects
in dogs. Bioorg. Med. Chem. Lett. 1996, 6 (4), 463-466.
(13) (a) Brown, G. R.; Foubister, A. J .; Freeman, S.; McTaggart, F.;
Mirrless, D. J .; Reid, A. C.; Smith, G. J .; Taylor, M. J .; Thomason,
D. A.; Whittamore, P. R. O. Novel optimised quinuclidine
squalene synthase inhibitors. Bioorg. Chem. Lett. 1997, 7, 597-
600. (b) Brown, G. R.; Clarke, D. S.; Foubister, A. J .; Freeman,
S.; Harrison, P. J .; J ohnson, M. C.; Mallion, K. B.; McCormick,
J .; McTaggart, F.; Reid, A. C.; Smith, G. J .; Taylor, M. J .
Synthesis and activity of a novel series of 3-biarylquinuclidine
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2979.
Ta ble 2. In Vivo Activity of A-87049 in Monkeys (20 mg/kg/
day for 5 days)
% change (from pretreatment control)a
5c (A-87049)
lovastatin
total cholesterol
HDL cholesterol
LDL cholesterol
-12 ( 1*
-4 ( 2
-36 ( 10*
-19 ( 9*
-12 ( 5
-21 ( 16
a
An asterisk (*) denotes values significantly different from zero
in one-sample t-test (p < 0.02).
change within a group across the experiment. Com-
pound 5c caused a statistically significant decrease in
total plasma cholesterol of 12% and LDL cholesterol of
36%, compared to pretreatment values. There was no
significant change in HDL cholesterol. Similar results
were obtained with lovastatin (Table 2). Plasma drug
level analysis revealed no circulating drug (limit of
detection ) 100 ng/mL), suggesting that 5c is cleared
rapidly from the plasma.
In summary, several potent squalene synthase inhibi-
tors have been identified. Their inhibitory potencies
were very significant (13-37 nM) in the rat liver
microsomal enzyme assay. Daily po administration of
20 mg/kg of A-87049 (5c) for 5 days in cynomolgus
monkeys (n ) 4) resulted in approximately 12% de-
crease in total cholesterol and 36% in LDL cholesterol,
while HDL cholesterol and triglycerides20 remained
unchanged. Further work on A-87049 (inhibition of
cholesterol biosynthesis and oral efficacy in other spe-
cies) and its more potent analogs is underway to confirm
the clinical utility of these inhibitors.
Ack n ow led gm en t. The authors thank Dr. XiaoLin
Zhang for NMR analysis of compounds 5d and 6d , Dr.
Rodger Henry for X-ray crystallographic analysis, and
Dr. J ohn Granger for the in vivo lipids assay of A-87049.
(14) Compound 4m was alternately prepared by replacing sodium
cyanoborohydride with Pd/C and 1 atm of H2. The yield was
95%.
(15) (a) Aldehyde intermediate for 4f: Harling, J ohn; Orlek, Barry
Sidney. (SmithKline Beecham PLC, UK). PCT Int. Appl. WO
9504027, p 57. (b) Aldehyde intermediate for 4g: Guziec, Frank
S.; Luzzio, Frederick A. J . Org. Chem. 1982, 47, 1787-1789. All
the other aldehyde intermediates are commercial products
obtained from Aldrich Chemical Co.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
procedures, NMR data, and analytical data for the final
products (11 pages). Ordering information is given on any
current masthead page.
Refer en ces
(1) Poulter, C. D.; Rilling, H. C. In Biosynthesis of Isoprenoid
Compounds; Porter, J . W., Spurgeon, S. L., Eds.; Wiley: New
York, 1981; Vol. 1., pp 413-441.
(16) The dianhydride was obtained from Aldrich.
(17) The isomeric structures of 5 and 6 are determined by 1H NMR
analyses. Furthermore, the 1,3-isomer 6d (where R ) Me and
R3 ) 4-phenoxybenzyl; see Scheme 2) is confirmed by X-ray
crystallography. The total yield of both isomers of all inhibitors
are approximately 70-80% except 5a and 6a isomers whose total
yield is only 10%.
(2) The Lipid Research Clinics Coronary Primary Prevention Trial
Results. J . Am. Med. Assoc. 1984, 251, 351-374.
(3) J oly, A.; Edwards, P. A. Biological effects of isoprenoids. Curr.
Opin. Lipidol. 1991, 2, 283-287.
(4) For recent reviews, see: (a) Biller, S. A.; Neuenschwander, K.;
Ponpipom, M. M.; Poulter, C. D. Squalene synthase inhibitors.
Curr. Pharm. Des. 1996, 2, 1-40. (b) Abe, I.; Tomesch, J . C.;
Wattanasain, S.; Prestwich, G. D. Inhibitors of squalene bio-
synthesis and metabolism. Nat. Prod. Rep. 1994, 279-302.
(5) Biller, S. A.; Forster, C.; Gordon, E. M.; Harrity, T.; Rich, L. C.;
Marretta, J .; Ciosek, C. P., J r. Isoprenyl phosphinylformates:
New inhibitors of squalene synthase. J . Med. Chem. 1991, 34,
1912-1916.
(18) Baker, W. R.; Rosenberg, S. H.; Fung, A. K. L.; Rockway, T.;
Fakhoury, S.; Garvey, D.; Donner, B. G.; O’Connor, S. J .; Prasad,
R.; Shen, W.; Stout, D.; Sullivan, G. Inhibitors of Squalene
Synthetase WO 95/12572, 1995.
(19) The IC50 of the 1,3-isomer (6c) is 1200 nM.
(20) Data not shown.
J M970058X