Conformational flexibility is a major determinant of the properties of macrocycles and other drugs in beyond rule of 5 (bRo5) space. Prediction of conformations is essential for design of drugs in this space, and we have evaluated three tools for conformational sampling of a set of 10 bRo5 drugs and clinical candidates in polar and apolar environments. The distance-geometry based OMEGA was found to yield ensembles spanning larger structure and property spaces than the ensembles obtained by MOE-LowModeMD (MOE) and MacroModel (MC). Both MC and OMEGA but not MOE generated different ensembles for polar and apolar environments. All three conformational search methods generated conformers similar to the crystal structure conformers for 9 of the 10 compounds, with OMEGA performing somewhat better than MOE and MC. MOE and OMEGA found all six conformers of roxithromycin that were identified by NMR in aqueous solutions, whereas only OMEGA sampled the three conformers observed in chloroform. We suggest that characterization of conformers using molecular descriptors, e.g., the radius of gyration and polar surface area, is preferred to energy- or root-mean-square deviation-based methods for selection of biologically relevant conformers in drug discovery in bRo5 space.

Novel P2X 7 Receptor Antagonists. -The synthesis and pharmacological evaluation of a series of novel cyclic imides that are potent P2X 7 receptor antagonists is disclosed. -(ALCARAZ*, L.; et al.; Bioorg. Med. Chem. Lett. 13 (2003) 22, 4043-4046; Dep. Med. Chem., Astra Charnwood, Loughborough, Leicestershire LE11 5RH, UK; Eng.) -H. Haber

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Background and purpose: The ATP-gated P2X 7 receptor has been shown to play a role in several inflammatory processes, making it an attractive target for anti-inflammatory drug discovery. We have recently identified a novel set of cyclic imide compounds that inhibited P2X 7 receptor-mediated dye uptake in human macrophage THP-1 cells. In this study the actions and selectivity of one of these compounds, AZ11645373, were characterized. Experimental approach: We measured membrane currents, calcium influx, and YOPRO-1 uptake from HEK cells expressing individual P2X receptors, and YOPRO1 uptake and interleukin-1b release from THP-1 cells in response to ATP and the ATP analogue benzoylbenzoyl ATP (BzATP). Key results: AZ11645373 up to 10 mM, had no agonist or antagonist actions on membrane currents due to P2X receptor activation at human P2X 1 , rat P2X 2 , human P2X 3 , rat P2X 2/3 , human P2X 4 , or human P2X 5 receptors expressed in HEK cells. AZ11645373 inhibited human P2X 7 receptor responses in HEK cells in a non-surmountable manner with K B values ranging from 5 -20 nM, with mean values not significantly different between assays. K B values were not altered by removing extracellular calcium and magnesium. ATP-evoked IL-1b release from lipopolysaccharide-activated THP-1 cells was inhibited by AZ11645373, IC 50 ¼ 90 nM. AZ11645373 was 4 500-fold less effective at inhibiting rat P2X 7 receptor-mediated currents with less than 50% inhibition occurring at 10 mM. Conclusions and implications: AZ11645373 is a highly selective and potent antagonist at human but not rat P2X 7 receptors and will have much practical value in studies of human cells.

The thiopeptide (or thiostrepton) antibiotics are a class of sulfur containing highly modified cyclic peptides with interesting biological properties, including reported activity against MRSA and malaria. Described herein is the total synthesis of the thiopeptide natural product amythiamicin D, which utilizes a biosynthesis-inspired hetero-Diels-Alder route to the pyridine core of the antibiotic as a key step. Preliminary studies using a range of serine-derived 1-ethoxy-2-azadienes established that hetero-Diels-Alder reaction with N-acetylenamines proceeded efficiently under microwave irradiation to give 2,3,6-trisubstituted pyridines. The thiazole building blocks of the antibiotic were obtained by either classical Hantzsch reactions or by dirhodium(II)-catalyzed chemoselective carbene N-H insertion followed by thionation, and were combined to give the bis-thiazole that forms the left-hand fragment of the antibiotic. The key Diels-Alder reaction of a tris-thiazolyl azadiene with benzyl 2-(1-acetylaminoethenyl)thiazole-4-carboxylate gave the core tetrathiazolyl pyridine, which was elaborated into the natural product by successive incorporation of glycine and bis-thiazole fragments followed by macrocyclization.

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