metastatic breast cancer. There have been no reports of an increase in the incidence of hot flashes with 33 during phase I or II trials.

Bury and co-workers have recently reported chromane-derived compounds which act as SERMs ( ). The lead compound in the series, NNC 45-0781 (35), is structurally related to lasofoxifene (34), which is currently in clinical development.83

Structure-activity relationship studies indicated that the C3 aryl ring is tolerant of ubstitution, and increased affinity was seen with both para- and meta-hydroxyl groups. The enantiomers were then separated, and for each compound examined, one enantiomer demonstrated significantly higher affinity. The parent compound, ( — ) 35, which was a high-affinity estrogen receptor ligand (IC50 = 2 nmol L— 1, rabbit uterine cytosol), was further evaluated in a series of in vivo assays. In an OVX rat bone assay, chromane (35) was shown fully to prevent volumetric bone mineral density loss from the proximal tibia at oral doses of 10 nmol g— 1 per day. Additionally, 35 prevented OVX-induced increases in osteoclast numbers, as evaluated by changes in tartrate-resistant acid phosphatase. Total serum cholesterol was also lowered with compound 35 at doses of 10 nmol g— 1 and higher compared to OVX animals. Positive effects were also observed on levels of endothelial nitric oxide synthase expression, which is speculated to play a role in the atheroprotective effect of estrogen. Beneficial effects were also observed with the maturation of vaginal mucosa; these were similar to the effects of E2 treatment. In OVX rats, the compound caused a reduction in uterine wet weight and had a nonproliferative effect on uterine epithelia.

In related work, two thio-substituted chromanes were prepared which contained either a pyrrolidine or piperidine basic side chain (Figure 18).84 The compounds were shown to have similar estrogen receptor binding affinity to other, nonsteroidal ligands such as raloxifene, and were partial agonists in Ishikawa human endometrial adenocarcinoma cells. For example, chromane 36 (estrogen receptor binding IC50 = 6.5 nmol L— 1, rabbit uterine cytosol) had a maximal agonist efficacy of 5% relative to moxestrol, with an EC50 of 0.5 nmol L — 1. The oxy-substituted analog (7) 35 bound to estrogen receptor with lower affinity (IC50 = 19 nmol L— 1) and was a more efficacious agonist in the Ishikawa cellular assay (EC50 = 0.9 nmol L — 1; Emax = 36%).

The introduction of flexibility into the rigid tamoxifen TPE core has been recently investigated.85 A series of compounds which contained a methylene spacer between the ethylene group and phenyl rings was prepared in an

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