Hypocholesteremic agents. I. Substituted stilbazoles and dihydrostilbazoles

Villani, Frank J.; Ellis, Claire A.; Tavares, Robert F.; Steinberg, Merl; Tolksdorf, Sibylle

doi:10.1021/jm00297a006

Cited by 9 publications

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“…1‐(3‐Methoxyphenyl)butan‐2‐one (18 b) : The crude compound was purified by column chromatography (eluent: from 0 to 15 % EtOAc in pet. ether) to give a colourless oil (257 mg, 50 %) which showed: [35] 1 H NMR (500 MHz, CDCl 3 ): δ =1.02 (3H, t, J =7.3 Hz, CH 2 C H 3 ), 2.47 (2H, q, J =7.3 Hz, C H 2 CH 3 ), 3.65 (2H, s, ArCH 2 ), 3.80 (3H, s, OCH 3 ), 6.73–6.77 (1H, m, ArCH), 6.77–6.84 (2H, m, 2×ArCH) and 7.24 (1H, t, J =8.0 Hz, ArCH) ppm. 13 C NMR (126 MHz, CDCl 3 ): δ =7.8 (CH 2 C H 3 ), 35.1 ( C H 2 CH 3 ), 49.9 (ArCH 2 ), 55.2 (OCH 3 ), 112.4 (ArCH), 115.0 (ArCH), 121.7 (ArCH), 129.7 (ArCH), 135.9 (Ar C CH 2 ), 159.8 (ArCO) and 208.9 (CH 2 CO) ppm.…”

Section: Methodsmentioning

confidence: 99%

N‐Phenyl‐1,2,3,4‐tetrahydroisoquinoline: An Alternative Scaffold for the Design of 17β‐Hydroxysteroid Dehydrogenase 1 Inhibitors

et al. 2020

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Abstract17β‐Hydroxysteroid dehydrogenases catalyse interconversion at the C17 position between oxidized and reduced forms of steroidal nuclear receptor ligands. The type 1 enzyme, expressed in malignant cells, catalyses reduction of the less‐active estrone to estradiol, and inhibitors have therapeutic potential in estrogen‐dependent diseases such as breast and ovarian cancers and in endometriosis. Synthetic decoration of the nonsteroidal N‐phenyl‐1,2,3,4‐tetrahydroisoquinoline (THIQ) template was pursued by using Pomeranz‐Fritsch‐Bobbitt, Pictet‐Spengler and Bischler‐Napieralski approaches to explore the viability of this scaffold as a steroid mimic. Derivatives were evaluated biologically in vitro as type 1 enzyme inhibitors in a bacterial cell homogenate as source of recombinant protein. Structure‐activity relationships are discussed. THIQs possessing a 6‐hydroxy group, lipophilic substitutions at the 1‐ or 4‐positions in combination with N‐4′‐chlorophenyl substitution were most favourable for activity. Of these, one compound had an IC50 of ca. 350 nM as a racemate, testifying to the applicability of this novel approach.

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Section: Methodsmentioning

confidence: 99%

N‐Phenyl‐1,2,3,4‐tetrahydroisoquinoline: An Alternative Scaffold for the Design of 17β‐Hydroxysteroid Dehydrogenase 1 Inhibitors

et al. 2020

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“…Sch 9122 HCl decreased serum cholesterol by 3570 at a dose of 10 mg/kg in Expt. 1 (Table I ) and by 23% at 5 mgfig in Expt. 2 (Table IT).…”

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confidence: 88%

Effects of Sch 9122 HCl, a Hypocholesterolemic Compound, on Mammary Tissue, Libido, and Fertility of Male Rats

Steinberg¹,

Watnick²

1970

Experimental Biology and Medicine

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It has been reported (1) that Sch 9122 HCl (2-(p-anisyl) -3-(2-pyridyl) -pentane hydrochloride), a compound structurally related to diethylstilbestrol, lowers serum cholesterol when administered. orally to rats. The oral dose which lowers cholesterol by 30% (ED30 cholesterol) in both normal male and ovariectomized rats is approximately 5 mgjkg. At the ED30 cholesterol, the compound did not reduce seminal vesicle weights and produced no estrogenic stimulation of the uterus or vagina. Sch 9122 HCl was much less estrogenic than conjugated equine estrogen, ethinyl estradiol, or diethylstilbestrol at comparable hypocholesterolemic doses. However, the predominant side-effects that limit the clinical usefulness of estrogenic compounds for the reduction of serum cholesterol are swelling and tenderness of the breast and adverse effects on libido and sexual performance. I t was, therefore, decided to compare directly in the rat the effects of chronically-administered Sch 9 122 HCl and several estrogens on pertinent activities which might reflect these undesirable side effects: mammary development, mating behavior, and fertility. The results of these investigations are reported below.Methods. Compounds were administered daily by gavage to normal adult male Charles River rats, CD strain, at doses (ED30) that produced approximately equal hypocholesterolemic responses in acute experiments: Expt. 1 (75 days) Dose Treatment (mg/kg, PO) No. of rats Sch 9122 HCl 10.0 6 Ethinyl estradiol 0.05 8 Diethylstilbestrol 0.20 6 10 Controls -Expt. 2 (100 dnys) nose Treat.mtw t (nig/kg, PO) No. of ra.t.s Sch 9123 HCl 5.0 Conjugated equine 0.5 Controls estrogenThe compounds were suspended in an aqueous medium containing carboxymethyl cellulose (O.OS%), benzyl alcohol (0.5 %) , and Tween 80 (0.25%). The controls received the vehicle alone.After 44 and 65 days in Exp. 1, and after 41 and 90 days in Expt. 2, the male rats were housed individually for 8 days with randomly selected adult female Charles River rats during which time drug treatment was continued. Daily vaginal smears were inspected for the presence of sperm. Females which had mated the previous evening were considered to be in the first day of pregnancy. The uteri were inspected for nidation sites on day 8 of pregnancy as evidence for male fertility. At the end of the treatment period, i.e., 75 or 100 days, the male rats were sacrificed and the testes, prostate, and seminal vesicles were removed and weighed to the nearest milligram. In Expt. 2, these organs were placed in 10% formalin and saved for subsequent histological examination (hemotoxylin and eosin). Samples of subcutaneous fat from the mammary region were also removed in Expt. 2, and the degree of estrogenic stimulation of mammary gland growth or development was determined his tologically.Serum cholesterol (2) and blood glucose ( 3 ) were determined using the Technicon Au tohalyser.A one-way, completely randomized analy-696 by guest on July 24, 2015 ebm.sagepub.com Downloaded from

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“…Derivatives of 10,11-Dihydro-5/f-dibenzo [a,d\cycloheptene and Related Compounds. 6. Aminoalkyl Derivatives of the Aza Isosteres"f" Frank J. Villani,* Peter J. L. Daniels, Claire A. Ellis, Thomas A. Mann, Kai-Chih Wang, and Elizabeth A. Wefer Department of Medicinal Chemistry, Schering Corporation, Bloomfield, New Jersey 07003.…”

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confidence: 99%

“…Received August 27,1971 The synthesis, antianaphylactic and antihistaminic potency, and structure-activity relationships of a series of aminoalkyl derivatives of the aza isosteres of 10,1 l-dihydro-5/f-dibenzo[a,d]cycloheptene are described. Compound 33, azatadine dimaleate, 6,11-dihydro-11 -(1 -methyl-4-piperidylidene>5/f-benzo- [ 5,6]cyclohepta[1,2-6]pyridine, conveniently designated as a member of the 4-aza-10,11-dihydrodibenzocycloheptene series, has shown very potent biological properties which have been confirmed in clinical trials in man.…”

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confidence: 99%

“…In the 4-aza series, i.e., those compounds wherein the pyridyl nitrogen is attached to a carbon atom which is a to the carbinol group, vigorous dehydrating conditions are required. 6 In these cases prolonged heating at 160-165°in the presence of excess PPA or the use of 85% H2S04 is necessary to effect the dehydration. A number of the compounds listed in Table II were obtained as a mixture of the cis and trans isomers and no effort was made to separate the mixture for preliminary biological evaluation.…”

mentioning

confidence: 99%

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Derivatives of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene and related compounds. 6. Aminoalkyl derivatives of the aza isosteres

Villani¹,

Daniels²,

Ellis³

et al. 1972

J. Med. Chem.

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Hypocholesteremic agents. I. Substituted stilbazoles and dihydrostilbazoles

Cited by 9 publications

References 0 publications

N‐Phenyl‐1,2,3,4‐tetrahydroisoquinoline: An Alternative Scaffold for the Design of 17β‐Hydroxysteroid Dehydrogenase 1 Inhibitors

N‐Phenyl‐1,2,3,4‐tetrahydroisoquinoline: An Alternative Scaffold for the Design of 17β‐Hydroxysteroid Dehydrogenase 1 Inhibitors

Effects of Sch 9122 HCl, a Hypocholesterolemic Compound, on Mammary Tissue, Libido, and Fertility of Male Rats

Derivatives of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene and related compounds. 6. Aminoalkyl derivatives of the aza isosteres

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