Raloxifene derivatives

The main source of data for raloxifene derives from the MORE study. A twofold increased risk for VTED was observed through 4 years of followup (Delmas et al. 2002), and, as for HT and tamoxifen, an accumulation of events occurred during the first year. 

The Suzuki-Miyarua reaction at the C3 position of benzothiophenes were shown to be useful in producing raloxifene derivatives such as des-keto-raloxifene. ... 

Zajchowski et al. [107] showed comparison of expression profiles between 38 different estrogen receptor-modulating compounds. An intial study was run based on the results of profiling of 24 combinations of cells and genes with estrogen, tamoxifen, raloxifene and ICI 164384 (a pure ER antagonist). Using the optimized assay panel derived from these studies, the 38 compounds were then profiled and classi-... 

Obviously, the effects of tamoxifen and derivatives and of raloxifene on L-type calcium channels from aortic and other blood vessels would reduce vascular smooth muscle contractility. This action, in synergy with the aforementioned effect on BK channels, would reduce blood peripheral resistance and blood pressure, which may partially account for the reduction in cardiovascular risk (Da Costa et al. 2004 Trump et al. 1992) (Fig. 4.1). 

Raloxifene hydrochloride is a synthetic nonsteroidal drug derived from the benzothiophene and afferent to SERMs. It is known that raloxifene acts on metabolism, the skeleton, and the cardiovascular system as an estrogenic agonist (Khovidhunkit et al. 1999 Ettinger et al. 1999 Walsh et al. 1998), whereas it shows an estrogenic antagonist effect on reproductive organs such as the... 

The benzothiophene derivative raloxifene (Evista /Lilly) is a selective estrogen receptor modulator (SERM). Raloxifene produces its biological actions via modulation (both activation and blockade) of estrogen receptors that ultimately results in decreased resorption of bone. The bisphosphonate derivative alendronate (Fosamax /Merck), an inhibitor of osteoclast-mediated bone resorption, is also useful in the treatment of osteoporosis. Both raloxifene and alendronate are useful in the treatment of osteoporosis in postmenopausal women. 

The three-dimensional structure of the ER was resolved by Brzozowski et al. [61]. Four additional X-ray structures of the receptor liganded with different molecules - estradiol, diethylstilbestrol, a nonsteroidal stilben derivative, and two antagonists raloxifen and 4-hydroxytamoxifen - were also solved [61, 62]. The availability of several structurally diverse structures bound to the active site of the receptor provided important experimental information detailing the molecular alignment of the studied molecules. 

CHF 4227 (Figure 5.23) is a benzopyran derivative that binds ERa and ER 3 with high affinity, and exhibits an improved SERM profile. In rats, CHF 4227 inhibited estrogenic effects on uterine weight gain about 25-fold more potently than raloxifene, while also preventing ovariectomized induced bone mineral density loss and an... 

Hepatic metabolism of tamoxifen produces N-desmethyltamoxifen, which has affinity for ER comparable to that of tamoxifen, and lesser amounts of the highly active metabolites 4-hydroxytamoxifen and endoxifen, which have 25-50 times higher affinity for both ERa and ERfi. Raloxifene is a nonsteroidal, polyhydroxylated conpound. Clomiphene has two isomers zuclomiphene (cis-clomiphene), a weak estrogen agonist, and enclomiphene (tcans-clomiphene), a potent antagonist. Fulvestrant is a 7a-alkylamide derivative of estradiol. 

This methodology was used by researchers at Eli Lilly to generate benzothiophene derivatives of tamoxifen. The cyclization and rearrangement reaction to produce the desired 2-aryl benzothiophene derivatives were promoted by polyphosphoric acid (PPA). These 2-aryl benzothiophene were then subjected to several additional transformations to produce LYl 56758 (raloxifene). 

In pursuit of additional derivatives, Eli Lilly scientists sought to synthesize constrained analogues of raloxifene. The synthesis of these analogues used a unique method of constructing the benzothiophene ring system through an acid-promoted dehydrative carbocationic cyclization of the hydroxythioacetamide using methanesulfonic acid as illustrated below. 

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