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1 This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor. 2 Lumiracoxib inhibited purified COX-1 and COX-2 with K i values of 3 and 0.06 mM, respectively. In cellular assays, lumiracoxib had an IC 50 of 0.14 mM in COX-2-expressing dermal fibroblasts, but caused no inhibition of COX-1 at concentrations up to 30 mM (HEK 293 cells transfected with human COX-1). 3 In a human whole blood assay, IC 50 values for lumiracoxib were 0.13 mM for COX-2 and 67 mM for COX-1 (COX-1/COX-2 selectivity ratio 515). 4 Lumiracoxib was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h. 5 Ex vivo, lumiracoxib inhibited COX-1-derived thromboxane B 2 (TxB 2 ) generation with an ID 50 of 33 mg kg À1, whereas COX-2-derived production of prostaglandin E 2 (PGE 2 ) in the lipopolysaccharidestimulated rat air pouch was inhibited with an ID 50 value of 0.24 mg kg À1 . 6 Efficacy of lumiracoxib in rat models of hyperalgesia, oedema, pyresis and arthritis was dosedependent and similar to diclofenac. However, consistent with its low COX-1 inhibitory activity, lumiracoxib at a dose of 100 mg kg À1 orally caused no ulcers and was significantly less ulcerogenic than diclofenac (Po0.05). 7 Lumiracoxib is a highly selective COX-2 inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with diclofenac, the reference NSAID, but with much improved gastrointestinal safety. British Journal of Pharmacology (2005) 144, 538-550. doi:10.1038/sj.bjp.0706078 Published online 17 January 2005 Keywords: Lumiracoxib; COX-2; cyclooxygenase-2 selective inhibitor; preclinical Abbreviations: AUC, area-under-curve of the concentration vs time curve; C max , maximum drug plasma concentration; CFA, complete Freund's adjuvant; 51 Cr-EDTA, chromium-51 labelled EDTA; COX, cyclooxygenase; D 30 , dose at which 30% inhibition was achieved; DMSO, dimethyl sulphoxide; F 0 , fraction of uninhibited enzyme at equilibrium; GI, gastrointestinal; HEK, human embryonic kidney; IL-1, interleukin-1; K i , inhibitor constant; k on , second-order rate constant representing speed at which an inhibitor binds to an enzyme; I, inhibitor concentration; LC/MS/MS, liquid chromatography/mass spectrometry/mass spectrometry; LPS, lipopolysaccharide; NSAID, nonsteroidal anti-inflammatory drug; O 2 , oxygen; PGE 2 , prostaglandin E 2 ; s, arachidonic acid concentration; t 1/2 , half-life; t opt , time to optimal velocity; TxB 2 , thromboxane B 2 ; V 0 , velocity in the absence of inhibitor; V obs , observed velocity in the presence of inhibitor; V opt , highest observed O 2 consumption velocity; V max , Michaelis-Menten constant for the maximal calculated velocity

The highly exothermic nature of Reformatsky reagent formation and the reported unpredictability of the induction time for its formation pose challenging problems for scaling up Reformatsky reactions. A zinc-activation procedure using DIBAL-H was developed and investigated using reaction calorimetry along with subsequent parts of the process. This procedure was shown to have important advantages for scale-up relative to previous zinc activation methods, including an immediate start of Reformatsky reagent formation with addition-controlled reaction. Calorimetric analysis was especially useful in specifying quickly a suitable temperature for Reformatsky reagent formation. The process was scaled up successfully.

The carbanionic ring enlargement of (halomethylene)cyclobutanes to 1-halocyclopentenes has been extended to the fluoro analogues. At 180 °C, 3-hexyl-1-(fluoromethylene)cyclobutane provides better yields of rearranged product than the corresponding chloride, bromide, or iodide. At temperatures < 100 °C, the yield of ring-enlarged product follows the order I > Br > Cl, and the fluoride does not react. Experiments with labeled substrates show that, in general, the larger the halide and the higher the reaction temperature, the greater the preference for double migration over single migration as a mechanistic pathway. The trifluormethyl group is ineffective in promoting anionic rearrangement.

Two syntheses of the class-selective histone deacetylase inhibitor 1 are reported. In the first, eight-step entailing synthesis, the key transformations were a highly efficient [3 + 2] dipolar cycloaddition affording trans-rac-5 and its resolution. In the second, asymmetric approach, the key steps were a highly selective asymmetric hydrogenation to produce the cis-(S,S)-3,4-disubstituted pyrrolidine 18 followed by an amide formation with simultaneous chiral inversion of the carboxy stereocenter to generate the key intermediate trans-(R,S)-3,4-disubstituted pyrrolidine 19. The overall yield increased from ∼6% for the resolution approach to ∼26% for the enantioselective approach.

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The unusual base-induced ring-enlargement of halomethylenecyclobutanes to 1-halocyclopentenes was examined with unsymmetrical and (13)C-labeled substrates to study regio- and stereochemical characteristics. Migration of a ring carbon atom (single migration) or simultaneous migration of a ring carbon atom and the halide (double migration) gives the ring-enlarged products. (13)C-labeling experiments established that both rearrangements occur with retention of configuration at the migrating center. These systems are suggested as models for the Fritsch-Buttenberg-Wiechell (FBW) rearrangement.

3,6‐Diarylidene‐2,5‐piperazinediones (2) and 3‐alkylidene‐6‐arylidene‐2,5‐piperazinediones (6) were synthesized from diacetyl‐2,5‐piperazinedione (1) under solid‐liquid phase transfer catalytic conditions. 2 could be easily convered to α‐amino acid by reducing with zinc powder and hydrolyzing with concentrated hydrochloric acid. The effect of different phase transfer catalysts and reaction conditions were studied.