Indole synthesis: a review and proposed classification

There is a medical need for an agent with the positive effects of estrogen on bone and the cardiovascular system, but without the negative effects on reproductive tissue. Raloxifene (LY139481 HCI) is a benzothiophene derivative that binds to the estrogen receptor and inhibits the effects of estrogen on the uterus. In an ovariectomized (OVX) rat model we investigated the effects of raloxifene on bone loss (induced by estrogen deficiency), serum lipids, and uterine tissue. After oral administration of raloxifene for 5 wk (0.1-10 mg/kg per d) to OVX rats, bone mineral density in the distal femur and proximal tibia was significantly greater than that observed in OVX controls (ED50 of 0.03-0.3 mg/kg). Serum cholesterol was lower in the raloxifene-treated animals, which had a minimal effective dose of 0.1 mg/kg and an approximate oral ED50 of 0.2 mg/kg. The effects of raloxifene on bone and serum cholesterol were comparable to those of a 0.1-mg/kg per d oral dose of ethynyl estradiol. Raloxifene diverged dramatically from estrogen in its lack of significant estrogenic effects on uterine tissue. Ethynyl estradiol produced a marked elevation in a number of uterine histologic parameters (e.g., epithelial cell height, stromal eosinophilia). These data suggest that raloxifene has promise as an agent with beneficial bone and cardiovascular effects in the absence of significant uterine effects.

/pdf/raloxifene-ly139481-hci-prevents-bone-loss-and-reduces-serum-1wtdlxwt9q.pdf

Raloxifene (LY139481 HCI) Prevents Bone Loss and Reduces Serum Cholesterol without Causing Uterine Hypertrophy in Ovariectomized Rats

Antiestrogens and Selective Estrogen Receptor Modulators as Multifunctional Medicines. 2. Clinical Considerations and New Agents

Since the description of the first antioestrogen, MER 25, more than four decades ago (Lerner et al. 1958), and of tamoxifen ten years later (Harper & Walpole 1967a,b), a large number of antioestrogens with diverse chemical structures have been described in the literature. The high level of interest in the synthesis and testing of new antioestrogens has been sustained by the therapeutic and commercial success of tamoxifen in the treatment of breast cancer. More recently, the first demonstration that tamoxifen can reduce the incidence of breast cancer in healthy women at high risk of developing the disease (Fisher et al. 1998) and that raloxifene can prevent osteoporosis (Bryant & Dere 1998) have provided a new impetus for drug discovery. Of the many analogues of tamoxifen described, only one other, chlorotamoxifen (toremiphene, Kangas 1990), has been marketed for breast cancer whilst several others are in various stages of clinical evaluation (e.g. idoxifene, Coombes et al. 1995; droloxifene, Bruning 1992). These molecules have very similar chemical and pharmacological properties: they are all non-steroidal, triphenylethylene-derived structures and all are partial agonists (mixed agonist/antagonist activities). A number of other non-steroidal structures with antioestrogenic activity have been reported, including substituted tetrahydronaphthalenes (e.g. nafoxidene, Duncan et al. 1963; trioxifene, Jones et al. 1979), indole derivatives (e.g. zindoxifene, Stein et al. 1990; ZK 119010, von Angerer 1990), benzothiophenes (e.g. LY117018, Black & Good 1980; LY156758 (keoxifene), Clemens et al. 1983) and benzopyrans (Sharma et al. 1990, Grese et al. 1996). All of these antioestrogens share with tamoxifen the pharmacological characteristic of partial-agonist activity; thus, whilst they antagonise the trophic action of oestrogens, this activity is incomplete because each compound has intrinsic oestrogen-like stimulatory (agonist) activity in vivo. The effect of drug treatment is a balance between agonist and antagonist activity. Whilst the term ‘partial-agonist’ accurately conveys the idea that all of these antioestrogens have some oestrogenic activity, it does not adequately describe their complex organ, cell and

/pdf/similarities-and-distinctions-in-the-mode-of-action-of-52z2l3agen.pdf

Similarities and distinctions in the mode of action of different classes of antioestrogens.

Uterine bioassay of tamoxifen, trioxifene and a new estrogen antagonist (LY117018) in rats and mice

Acylation of the sodio anion of beta-tetralone with phenyl anisoate, followed by a Grignard reaction of the resultant 4 with 4-methoxyphenylmagnesium bromide, gave rise to two novel dihydronaphthalene isomers 5 and 6. Regioselective demethylation of either 5 or 6 by NaSEt produced [3,4-dihydro-2-(4-methoxyphenyl)-1-naphthalenyl](4-hydroxyphenyl)methanone (7). Etherification of the phenolic group of 7 by N-(2-chloroethyl)pyrrolidine and subsequent methanesulfonate salt formation provided [3,4-dihydro-2-(4-methoxyphenyl)-1-maphthalenyl]]4-]2-(1-pyrrolidinyl)ethoxy]phenyl]methanone, methane sulfonic acid salt (3). Potent antiestrogenic activity of 3 was demonstrated by both oral and subcutaneous administration to rats and mice. In vitro binding studies with rat uterine cytosol estrogen receptors indicate compound 3 has a very high binding affinity which exceeds that of estradiol.

Synthesis and antiestrogenic activity of [3,4-dihydro-2-(4-methoxyphenyl)-1-naphthalenyl][4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone, methanesulfonic acid salt

Direct synthesis of 2-acylindoles

Benzothiophenes 3 and 4, derived from the acrylophenone antiestrogen trioxifene (2), are characterized by high estrogen receptor (ER) affinity and low residual estrogenicity compared to tamoxifen (1a). In order to characterize further the growth suppression mechanism for these structural types we have prepared structural variants of 2 bearing hydroxy groups positioned to maximize ER affinity. Thus, dihydronaphthalenes 5 and 6 and benzofluorenes 7 and 8 were prepared and studied in MCF-7 human breast cancer cells, in comparison with 3 and 4. All compounds were powerful suppressants of cell growth, with 50% inhibition ranging from 4.5 to 160 nM. Greatest potency was seen with diphenols 6 and 8. These compounds had intracellular ER affinities ranging from 0.2 to 4.1% of that of estradiol, suggestive of a potential for partial agonist effects. Simultaneous exposure of cells to 0.1 microM concentrations of estradiol and 3 or 4 did not affect the degree of growth inhibition seen with 0.1 microM 3 or 4 alone. Partial reversal of inhibition occurred when 0.1 microM 5-8 were each accompanied by 0.1 microM estradiol. Under these conditions complete reversal of growth inhibition has been found with 1a, 1b, and other triarylethylenes. Calmodulin, a putative target for triarylethylenes, and which is antagonized by 1a, was shown to interact weakly with 7 and 8 and not at all with 3-6. These results suggest that MCF-7 cell growth suppression by 3-8 may be due to interaction with unidentified receptors besides ER and extend earlier findings indicating that events occurring after interaction of these compounds with ER differ from those of triarylethylene antiestrogens.

Antiestrogens. 3. Estrogen receptor affinities and antiproliferative effects in MCF-7 cells of phenolic analogues of trioxifene, [3,4-dihydro-2-(4- methoxyphenyl)-1-naphthalenyl][4-[2-(1-pyrrolidinyl)ethoxy]- phenyl]methanone.

A class of novel tricyclics is diclosed of the formula (I)
 
wherein;
 A is phenyl or pyridyl wherein the nitrogen is at the 5-, 6-, 7-
or 8-position; 
one of B or D is nitrogen and the other is carbon; Z is cyclohexenyl, phenyl, pyridyl, wherein the nitrogen is at
the 1-, 2-, or 3position, or a 6-membered heterocyclic ring having one
heteroatom selected from the group consisting of sulfur or oxygen at the
1-, 2- or 3-position, and nitrogen at the 1-, 2-, 3- or 4-position; ---- is a double or single bond; 
together with the use of such compounds for inhibiting sPLA 2 
mediated release of fatty acids for treatment of conditions such as septic
shock.

Substituted tricyclics useful in sPLA2 induced diseases

Nouveaux agents anti-fertilite

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