RESEARCH
New Chemicals Lower Blood Cholesterol Levels Dialkylaminoalkyl ethers of estrogens block liver's cholesterol biosynthesis in way similar to triparanol 142ND
ACS NATIONAL
MEETING
Medicinal Chemistry
Dialkylaminoalkyl ethers of many estrogens block biosynthesis of cholesterol by the liver. The findings may multiply the number of anticholesterol agents available for testing. Hypocholesteremic action of the estrogen ethers apparently is different from that of the estrogens themselves, say Dr. G. M. K. Hughes, Dr. S. K. Figdor, and co-workers at Chas. Pfizer & Co. Estrogens alter fatty components of blood, lower blood cholesterol, and increase levels of cholesterol in the liver. The estrogen ethers also lower
blood cholesterol, but they don't affect concentrations of sterols in the liver. Composition of the liver sterols is changed, though. The Pfizer group found large concentrations of desmosterol, not normally present, in the livers of rats treated with the estrogen ethers. This indicates that these compounds block conversion of desmosterol to cholesterol by the liver, Dr. Figdor says. More than 60 dialkylaminoalkyl ethers of estrogens have been synthesized by the Pfizer group. Most active is the ether of chlorinated ethyl cyanostilbene [ 3- (4-chlorophenyl) -2(4-diethylaminoethoxyphenyl) -cx-p e ntenonitrile], called P3429 by Pfizer. Tests indicate P3429 in rats is more than six times as active as triparanol
(Richardson-Merrell's MER/29). Other compounds in the Pfizer group are as potent as triparanol and are also longer acting, Dr. Figdor says. Triparanol has been withdrawn from the market because of undesirable side effects. Pfizer indicates that there is no evidence to suggest that these effects are a result of the way in which triparanol lowers cholesterol. Pfizer doesn't plan to market its new compounds now, since the more active ones also have some side effects. But, Pfizer says, the new drugs are interesting enough to warrant further studies which could lead to useful hypocholesteremic drugs.
Estrogens Used. The effort to find a way to lower cholesterol levels in blood is huge. The driving force is
Experimental Hypocholesteremics Have Relatively Long Action (Ethyl
cyanostilbene)
et
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2 4 6 8 10 12 14. 16 18 20 22 24 Hours after administration (tests made on rats) 54
C&EN
SEPT.
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mounting evidence—mostly circumstantial—that ties high cholesterol levels in blood to incidence of atherosclerosis. Much of the research effort is aimed at blocking the biosynthesis of cholesterol. Scientists have noted that premenopausal women are relatively immune to atherosclerosis. Thinking here is that estrogens somehow hold down cholesterol levels in blood. Estrogens reduce serum cholesterol. But, unfortunately, estrogens also have a feminizing effect. Research in this area is aimed at finding estrogen-related compounds that lower cholesterol but aren't feminizing. Chemically 1-p- (/?-diethylamino) ethoxyphenyl - 1 - (p-tolyl) -2- (p-chlorophenyl) ethanol, triparanol prevents saturation of the double bond between C-24 and C-25 of desmosterol and so blocks its conversion to cholesterol. Several other chemicals containing the diethylaminoalkyl group block cholesterol biosynthesis. Some of them apparently act at several places along the metabolic pathway to cholesterol instead of at the desmosterolto-cholesterol stage (C&EN, April 10, 1961, page 4 5 ) . Seek High Activity. After taking a hard look at triparanol, Pfizer scientists decided the diethylaminoethyl group gives it its unique activity. The corresponding phenol and methyl ether of triparanol are relatively inactive. Dr. Hughes' group noted that the diethylaminoethyl ether of 4-stilbeneol lowers blood cholesterol levels in rats, and livers of rats fed this chemical contain desmosterol. The same activity was seen with diethylaminoethyl ethers of estradiol, stilbesterol, and hexasterol. Following this lead, Dr. Hughes' group synthesized several aminoalkyl ethers of 4-stilbeneol. None is more active than the diethylaminoethyl ether. Promising activity was shown by diethylaminoethyl ethers of cyanostilbenes, especially when given by injection. Adding alkyl, halogen, nitrogen, and oxygen-containing groups on the benzene rings doesn't materially increase activity. Alkylthio substitution confers greater activity, as does adding a second diethylaminoethoxy group. Finally, putting an ethyl group on the double bond of diethylaminoethoxy cyanostilbene gives the most active series of compounds. To get a clear picture of the rela-
tive hypocholesteremic abilities of the more promising compounds, Dr. Figdor's group examined bisalkyl ether cyanostilbene and ethylcyanostilbene. These chemicals were compared with triparanol in vivo using rats and in vitro using rat livers and mevalonic acid. The in vivo studies show the bis ether to be more active than the ethylcyanostilbene, Dr. Figdor says. It lowers serum cholesterol to a greater degree, and livers of rats fed the bis compound contain more desmosterol. Neither compound is as active as triparanol in this test. But in vitro studies indicate the cyanoethylstilbene is more active than the bis compound, Dr. Figdor says. In this test, triparanol activity lay somewhere between the two Pfizer compounds. To resolve these differences and to learn the effects of absorption and transport on biosynthetic block, a timecourse study was done with rats. This study shows all three compounds are about equally active in vivo, Dr. Figdor notes, but the cyanostilbenes are longer acting. The bis compound reaches high concentrations in the liver and achieves high biosynthetic blocking—95%—in about six hours. These levels are maintained for another six hours. The cyanoethylstilbene hits peak activity in two hours and maintains it for an additional 10 hours. Triparanol hits peak activity in six hours, but its activity drops off relatively quickly.
Aldehydes Fight Urinary Tract Infections Two compounds under study yield antibacterial aldehydes at alkaline instead of acid pH 142ND
ACS
NATIONAL
MEETING
Medicinal C h e m i s t r y
Two new aldehyde-generating chemicals may point the way to more effective drugs against urinary tract infections. Now undergoing lab tests are Cidex, Ethicon's brand name for a lactone of glutaraldehyde, and KEF201, Commercial Solvents' designation for 2 - nitro - 2 - n - propyl -1,3 - dihydropropane, an analog of the widely used tranquilizer, meprobamate. Both
compounds are unique in that they yield antibacterial aldehydes at alkaline pH. Other widely used aldehydereleasing drugs require a pH below 6.0. The ability to work at high pH may make chemicals of this type useful against urea-splitting infections, says Dr. Hans H. Zinsser and co-workers at Columbia Presbyterian Medical Center. These infections are commonly found in the urinary tract. The bacteria involved split ammonia from urea in the urine. Result is an increase in pH to levels where presentday drugs lose much of their effect. No Resistance. The attack against urinary tract infections is built around getting high concentrations of aldehydes in the urine. Formaldehyde looms as very desirable because, to date, no organism has developed resistance against its antibacterial action, Dr. Zinsser says. Methenamine (hexamethylenetetramine) decomposes to formaldehyde at pH below 6.0, so it's widely used to treat urinary tract infections. Usually, though, urine isn't acid enough to cause bacteriostatic levels of formaldehyde to be generated. Therefore, various adjuvants are used along with methenamine. Included are such chemicals as mandelic acid, methionine, ammonium chloride, sulfonamides, mercurial diuretics, and even cranberry juice. Some of these are antibacterial in themselves; others are used only for their ability to acidify urine. But tests show that present-day drugs yield only a little aldehyde in the urine—not enough to account for the antibacterial action seen from the medication, Dr. Zinsser says. He feels that some mechanism other than aldehyde release is at work to give the results seen. But the new chemicals now being tested yield aldehydes at a rate directly proportional to the ammoniagenerating capabilities of ureasplitting bacteria. KEF-201 yields formaldehyde, highly antibacterial but somewhat irritating to human mucous membrane. Cidex generates glutaraldehyde, which is somewhat less irritating. Cidex itself hasn't been used internally since it is too irritating to mucous membrane at bactericidal concentrations. However, it may lead to chemically related compounds that arc effective glutaraldehyde generators, but which are less irritating, Dr. Zinsser says. SEPT.
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