Synthesis, SAR, and series evolution of novel oxadiazole-containing 5-lipoxygenase activating protein inhibitors: discovery of 2-[4-(3-{(r)-1-[4-(2-amino-pyrimidin-5-yl)-phenyl]-1-cyclopropyl-ethyl}-[1,2,4]oxadiazol-5-yl)-pyrazol-1-yl]-N,N-dimethyl-acetamide (BI 665915).

The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and potent inhibition of LTB4 synthesis in human whole blood (IC50 < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of compound 69 (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance.

Synthesis, structure and stereochemistry of quinoline alkaloids from Choisya ternata.

A range of seventeen quinoline alkaloids, involving several types of oxidations during their biosynthetic pathways, have been isolated from leaves of Choisya ternata. In addition to the nine known quinoline alkaloids, eight new members of the furoquinoline family, derived mainly from prenylation at C-5 (including two novel hydroperoxides), have been identified. The absolute configurations and enantiopurity values of all chiral quinoline alkaloids have been determined.

cis-Dihydrodiol, arene oxide and phenol metabolites of dictamnine: key intermediates in the biodegradation and biosynthesis of furoquinoline alkaloids.

Biotransformation of the parent furoquinoline alkaloid dictamnine and its 4-chlorofuroquinoline precursor, using the B8/36 bacterial mutant strain of Sphingomonas yanoikuyae, yielded, via biphenyl dioxygenase-catalysed dihydroxylation, the first isolable alkaloid cis-dihydrodiol metabolites; these metabolites were used in the chemoenzymatic synthesis of postulated arene oxide and phenol intermediates, and a range of derived furoquinoline alkaloids.

Absolute configuration assignment and enantiopurity determination of chiral alkaloids and coumarins derived from O- and C-prenyl epoxides.

A combination method of ozonolysis and chiral stationary phase (CSP)-GC-MS analysis has been developed to determine the enantiopurity values and absolute configurations of a range of alkaloid and coumarin hemiterpenoids derived from C- and O-prenyl epoxides.