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Oral Bioavailability, access to intracellular targets, cost, and ease of production are some of the reasons that small molecule drugs are very desirable in the industry. However, discovery and development of small molecules has not been facilitated, in spite of the mammoth advances in genomics, proteomics, and chemistry. The topic was discussed at Cambridge Healthtech's conference (Mastering Medicinal Chemistry') and the IBC High Throughput Chemistry conference. For instance, a step forward described was the effort by Merck to improve strand transfer screening assays for integrase before the team discovered a new series of integrase inhibitors. Medicinal chemists worked to improve potency, reduce protein binding matters, and increase solubility. A resulting carboxamide lead compound named L-870,810 met Merck's criteria for clinical development, and a Phase I study was begun. The results of a short, ten-day antiviral study in humans showed that there was good antiviral activity (a 1.7 log reduction) and no drug-related adverse events. However, Merck halted the development of L-870,810 after unexpected toxicity was seen in long-term dog strategies. Among topics covered are use of druggable space, and screening for activity and selectivity.
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