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We encountered a dilemma in the course of studying a series of antagonists of the G-protein coupled receptor CC chemokine receptor-2 (CCR2): compounds with polar C3 side chains exhibited good ion channel selectivity but poor oral bioavailability, whereas compounds with lipophilic C3 side chains exhibited good oral bioavailability in preclinical species but poor ion channel selectivity. Attempts to solve this through the direct modulation of physicochemical properties failed. However, the installation of a protonation-dependent conformational switching mechanism resolved the problem because it enabled a highly selective and relatively polar molecule to access a small population of a conformer with lower polar surface area and higher membrane permeability. Optimization of the overall properties in this series yielded the CCR2 antagonist BMS-741672 (7), which embodied properties suitable for study in human clinical trials.

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Hand picking, by snapping each fruit from its stem, has been the traditional method of harvesting Florida oranges (Citrus sinensis) and grapefruit (C. paradisi) for processing. A harvest mechanization program was active from about 1960 to 1985, but mechanical methods were not adopted. In July 1994, a new harvesting research and development program was initiated by the Florida Department of Citrus. The growers are taxed about $0.01/field box of production to fund the program. An industry Advisory Council oversees the program, and recommends projects and funding. The new program has provided training videos to improve hand harvest management/productivity, developed several methods for mechanical harvesting, and discovered/evaluated several fruit abscission agents. Mechanical harvesting use is increasing, and about 6880 of the 237,498 ha (17,000 of the 586,859 acres) of oranges were mechanically harvested during the 2002-03 season. Two mechanical systems can increase labor productivity by 5 to 15 times and reduce unit harvesting cost by 50% or more. Such savings are essential for effective competition in free-trade markets and for operation with resident labor. Many old-style plantings will need to be replaced over the next 10 years. The harvesting program accomplishments are discussed.

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We describe the hybridization of our previously reported acyclic and cyclic CC chemokine receptor 2 (CCR2) antagonists to lead to a new series of dual antagonists of CCR2 and CCR5. Installation of a γ-lactam as the spacer group and a quinazoline as a benzamide mimetic improved oral bioavailability markedly. These efforts led to the identification of 13d, a potent and orally bioavailable dual antagonist suitable for use in both murine and monkey models of inflammation.