Two virtual screening strategies, "query by bagging" (QBag) and "query by bagging with descriptor-sampling" (QBagDS), based on active learning were devised. The QBag strategy generates multiple structure-activity relationship rules by bagging and selects compounds to improve the rules. To find many structurally diverse hits, the QBagDS strategy generates rules by bagging with descriptor sampling. They can also use prior knowledge about hits to improve the efficiency at the beginning of screening. We performed simulation experiments and clustering analysis for several G-protein coupled receptors and showed that the QBag and QBagDS strategies outperform the conventional similarity-based strategy and that using both descriptor sampling and prior knowledge are effective for finding many hits. We applied the bagging with descriptor sampling strategy to novel hit finding, and 4 of the 10 selected compounds showed high inhibition.

Modifications to the ET(A/B) mixed type compounds 1 (Ro. 46-2005) and 2 (bosentan) were performed. Introduction of a pyrimidine group into 1 resulted in a dramatic increase in affinity for the ET(A) receptor, and the subsequent optimization of substituents on the pyrimidine ring led us to the discovery of N-(6-(2-((5-bromo-2-pyrimidinyl)oxy)ethoxy)-5-(4-methylphenyl)-4-pyrimidinyl)-4-tert-butylbenzenesulfonamide (7k), which showed an extremely high affinity for the human cloned ET(A) receptor (K(i) = 0.0042 +/- 0.0038 nM) and an ET(A/B) receptor selectivity up to 29 000 (K(i) = 130 +/- 50 nM for the human cloned ET(B) receptor). The compound was designed on the hypothesis that the hydrogen atom of the hydroxyl group in 1 and 2 played a role not as a proton donor but as an acceptor in the possible hydrogen bonding with Tyr129. Since the incorporation of a pyrimidinyl group into the hydroxyethoxy side chain of the nonselective antagonist (1) dramatically enhanced both the ET(A) receptor affinity and selectivity, and since similar results were obtained from the benzene analogues, we put forward the hypothesis that a "pyrimidine binding pocket" might exist in the ET(A) receptor.

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EtAlCl2 catalyzes the Cargill rearrangement of bicyclo[n.2.0] compounds which were prepared by the TiCl4-mediated [2+2] cycloaddition reaction of cycloalkenones and 1-t-butyldimethylsilyl-2-methylthioacetylene, yielding various bicyclo[n-1.2.1] compounds under mild reaction conditions.