Effects of SP500263, a novel selective estrogen receptor modulator, on bone, uterus, and serum cholesterol in the ovariectomized rat.

We describe here the activity of a novel selective estrogen receptor modulator, SP500263. When given to adult ovariectomized (OVX) rats for 28 days at doses of 0.3, 1, or 3 mg/kg/day, we found that SP500263 partially protected against OVX-induced loss of bone mineral content in the distal ends of femurs and in the whole bone. SP500263 also antagonized the OVX-induced increase in body weight. However, unlike 17beta-estradiol, SP500263 at efficacious doses did not prevent the OVX-induced loss in uterine wet weight. A small but significant effect on uterine wet weight was noted with raloxifene dosed at 1 mg/kg. As expected, SP500263 but not raloxifene acted as an estrogen antagonist on the uterus in adult rats when administered for 7 days at 30 mg/kg/day. Finally, SP500263 had no statistically significant effects on total serum cholesterol and serum triglycerides in OVX rats treated for 28 days. Raloxifene had no significant effects on body weight, bone mineral content, and serum cholesterol or triglycerides in the OVX-rat model. In summary, SP500263 is a new orally active SERM that acts in rats as an estrogen agonist on bone without causing uterine stimulatory effects.

Inhibitors of NF-kappaB and AP-1 gene expression: SAR studies on the pyrimidine portion of 2-chloro-4-trifluoromethylpyrimidine-5-[N-(3', 5'-bis(trifluoromethyl)phenyl)carboxamide].

We investigated the structure-activity relationship studies of N-[3, 5-bis(trifluoromethyl)phenyl][2-chloro-4-(trifluoromethyl)pyrimidin-5 -yl]carboxamide (1), an inhibitor of transcription mediated by both NF-kappaB and AP-1 transcription factors, with the goal of improving its potential oral bioavailability. Compounds were examined for cell-based activity, were fit to Lipinski's rule of 5, and were examined for potential gastrointestinal permeability using the intestinal epithelial cell line, Caco-2. Selected groups were substituted at the 2-, 4-, and 5-positions of the pyrimidine ring using solution-phase combinatorial methodology. The introduction of a fluorine in the place of 2-chlorine of 1 resulted in a compound with comparable activity. However, other substitutions at the 2-position resulted in a loss of activity. The trifluoromethyl group at the 4-position could be replaced with a methyl, ethyl, chlorine, or phenyl without a substantial loss of activity. The carboxamide group at the 5-position is critical for activity. If it was moved to the 6-position, the activity was lost. The 2-methyl analogue of 1 (81) showed comparable in vitro activity and improved Caco-2 permeability compared to 1.