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MEDICINAL CHEMISTRY557676 CHIMIA 2008, 62,No ANALYTICAL CHEMISTRY/MEDICINAL CHEMISTRY557676 CHIMIA 2008, 62,No. 7/8 Analytical Chemistry 73 Analytical Chemistry 74 IndicatorDisplacement Assays as MolecularTimers Real-time, on-linemonitoring of organic chemical reactions using ex- tractive electrosprayionization tandem mass spectroscopy FriederikeZaubitzer,Alexei Pozdnoukhov, Kay Severin* Liang Zhu1;Gerardo Gamez1;Huanwen Chen2;Haoxi Huang1;Konstantin 1 1 *Institut desSciences et Ingénierie Chimiques, EcolePolytechnique Chingin ;Renato Zenobi Fédérale de Lausanne (EPFL), CH-1015 Lausanne,Switzerland 1ETHZurich, Zurich,Switzerland; 2College of Chemistry, JilinUniversity, Indicatordisplacementsassays (IDAs) have emerged as powerful analytical Changchun, China tools. They arebased on dyes which compete with analytes for binding to 1 synthetic receptors.Sofar, IDAshave primarilybeen used to determine the Extractive electrospray ionization mass spectrometry (EESI-MS) for identity and/orthe quantity of certain analytes. real-time, on-line monitoring of organicchemicalreactions wasdemon- We show that amulticomponent IDAcan also be employed to obtain infor- stratedfor awell established pharmaceutical process reaction (one-step mation about the history of chemical inputs. Asimple mixture of three Michaeladdition reactionwith phenylethylamine (PEA) and acrylonitrile in ethanol)2 andawidely used acetylation reactioninthe presence of anuc- commercially available dyes and the organometallic complex [(Cp*RhCl2)2] 3 is employed to timethe addition of ADP and ATP with good resolution [1]. leophilic catalyst, 4-DMAP (multiple-step acetylation reaction of benzyl alcohol with acetic anhydride catalyzed by 4-DMAP in dichloromethane). EESI-MS,with acommerical quadrupole-time-of-flight (Q-TOF) mass spectrometer,provides real-timeinformation that allows determining the optimumtimefor terminating the reaction based on the relative intensities of the precursors and products. In addition, analysis viaEESI-MS permits on-line validation of proposedreaction transients,which appears during the catalytic pathway of 4-DMAP,relying on tandem MS. The relatively simple setup allows this method to be implemented on anytype of MS instrument with ESI /APCI interface. The EESI-MS features an instant response (<0.2s) and does not require sample pre-treatment, making it apowerful and con- venient toolfor on-line characterization and full controlofchemicaland Fig.1.: The ADP and ATP addition timesdeterminedbythe molecular timer in pharmaceutical reactions, resulting in maximized product yield and mini- comparison with the real addition times for 12 test samples. The predictions are mized environmental costs. shown as filled symbols (5 measurements each) and the real addition timed are [1]H.W.Chen, A. Venter and R. G. Cooks, Chem.Commun., 2006, indicatedbyempty symbols. 2042-2044 [2]R.Clinton, C. S. Creaser and D. Bryant, Anal.Chim. Acta., 2005,539, The signal of the timer is read by UV/Vis spectroscopy and the data is ana- 133-140. lyzedvia amultivariate analysis. [3]G.Hofle,W.Steglich and H. Vorbruggen, Angew.Chem., Int. Ed. Engl., 1978,17, 569-583. [1]A.Buryak, F. Zaubitzer,A.Pozdnoukhov, K. Severin, submitted. Analytical Chemistry 75 Medicinal Chemistry 76 Calcilytics ANew Treatment for Established Osteoporosis Total Synthesis of the Resorcylic Lactone-based Leo Widler KinaseInhibitorL-783277 Novartis InstitutesofBioMedicalResearch, WKL-136.3.93, CH-4002Basel, Switzerland Tatjana Hofmann, Karl-Heinz Altmann Osteoporosis is characterized by low bone mass andmicro-architectural deteriorationofbone tissue thatleads to fragility and increased risk of fractures. InstituteofPharmaceutical Sciences,ETH Zurich, Wolfgang-Pauli-Str. 10, Traditional therapiesfor osteoporosis inhibit bone resorption andprevent further 8093 Zurich, Switzerland bone loss.However,asmany osteoporosis patients have alreadylost asubstantial amount of bone at the time of diagnosis, thereisaneed for agents that stimulate Kinaseshave emerged as important drug targets in cancer and inflammatory newboneformation. The only anabolic treatment forosteoporosis, approvedfor diseaseand several low-molecular-weight kinase inhibitors have now been the US andEUmarkets, is Forteo®/Forsteo® (Teriparatide, the 1-34 fragment of introduced into clinicalpractice.[1] The natural product L-783277 (1)be- parathyroidhormone (PTH))which causes asignificant increase in bone mass and longs to the family of resorcylic acid lactones (RALs),which includes com- reduces vertebral fracture risk substantially. This peptide must be administered by pounds such as zearalenone, C292 (LL-Z1640-2), hypothemycin, or radici- daily subcutaneousinjection and the therapy is costly. An orally active, low col, and which exhibit adiverserangeofbiological activities.[2] L-783277 molecularweight compound with thesameefficacywould be ahighly attractive (1)isapotent inhibitor of the Ser/Thr kinase MEK.[3]Wehave accom- alternative for the patient. plished the first totalsynthesis of macrolactone 1,which is based on the Insteadofapplying exogenous PTH, mobilization of endogenous stores of the consecutiveassembly of the key fragments A, B,and C.[4] The develop- ment of an efficient enantioselective synthesis of 1 and amore detailed hormone can be envisaged. PTH is storedinrelatively large amounts in parathyroid characterizationofits biological effects are the primarygoals of this re- cells and its secretion is controlled by acalcium-sensing receptor (PCaR) located search project. This presentation will discuss the details of the synthesis of 1 on the cell surface. Antagonists of PCaR (calcilytics) mimic astate of and the preparation of anumber of analogs. Preliminary data on the in vitro hypocalcemiaand stimulate PTH release to the blood stream. biologically activity of these compounds will also be presented. The starting point for the Novartis calcilyticsproject was aproprietary structure found in aHTS screenusing afunctionalassay in the FLIPR format based on OTBS OTBS recombinant human PCaR. Optimization of the series resulted in an increase in in OH O OH O OH O vitro potencybyafactor of >100. First oral applicationsinrats with these highly C OR + O OR O potent calcilytics were rather disappointing with regard to PK/PD parameters. The OH presentation will focus in thesecond part on how these limitations were overcome. O Br O OH O O O O O O OH PK/PD datainrats anddogs will be shown that mark thebestofour derivatives A B D 1 attractive fordevelopment as oral calcilytics.There is excellent correlation of drug R=CH2CH2Si(CH3)3 L-783277 exposure andPTH release. High levels of PTH are reached in plasma within minutesinboth species after p.o.. application whichrevert to baseline in about 1-2 [1] Krause, D. S. and Van Etten, R. H. N. Engl. J. Med. 2005,353, 172-187. hours. This profile is aprerequisite for bone anabolic action, sinceitiswellknown [2] Winssinger, N. and Barluenga, S. Chem.Commun. 2007, 1,22-36. that persistently elevated levels of PTH stimulatenot only osteoblasts (bone [3] Zhao, A.; Lee, S. H.; Mojena, M.; Jenkins, R. G.; Patrick, D. R.; Huber, forming cells)but also osteoclasts, theboneresorbing cells. The net result is H. E.; Goetz, M. A.; Hensens, O.D.; Zink, D. L.; Vilella, D.; Dom- increased bone turnover rather than thedesired gain in bone mineral density browski, A. W.;Lingham, R. B.; Huang, L. J. Antibiot. 1999,52(12), (BMD). 1086-1094 [4] Hofmann,T.and Altmann, K.-H. Synlett 2008 in press MEDICINAL CHEMISTRY557777 doi:10.2533/chimia.2008.577 CHIMIA 2008, 62,No. 7/8 Medicinal Chemistry 77 Medicinal Chemistry 78 NMR Derived Binding Epitopes of Myelin-Associated-Glycoprotein TheFirst Nonpeptidic, SmallMolecule, Highly Selective Somatostatin 5 Antagonists Receptor Antagonists: AChemogenomics Approach BrianCutting1,DanielStrasser1,Sachin Shelke1,GanpanGao1,Oliver Rainer E. Martin,Luke G. Green, Wolfgang Guba,NicoleKratochwiland Schwardt1,Soerge Kelm2 andBeatErnst1,* AndreasChrist 1UniversityofBasel, Klingelbergstrasse50, CH-4056Basel, Switzerland Medicinal Chemistry III, Discovery Chemistry, F. Hoffmann-La RocheLtd, 2University of Bremen, Leobenerstr. NW2B2, D-28359 Bremen, Germany 4070 Basel, Switzerland Following injury to the adult CNS, regeneration is inhibited by asignal Somatostatin (SST) or somatotropin release-inhibiting factor (SRIF) is a transductionpathway initiatedbythree proteins, Nogo-A, Omgp andMAG, peptidehormonedistributed throughout the body exhibiting multiple bio- interacting with the Nogo receptor.Ithas been shown that blockingthe logical functions, including antisecretagogue, antiproliferative and neuro- bindingsite of MAG diminishes theinhibition of regeneration [1]. transmitteractivities. SST acts via five distinct G-proteincoupled receptors (SST1-5), which all have been cloned and characterized. Particularly, SST Herein, we provide an interpretation of the mode of binding of related MAG acting via SST5 receptors has beenfound to activate and up-regulate antagonists. This interpretation is achieved through asynergistic use of STD NMDA receptor functionand to control hormonal secretions (e.g.,growth NMR [2] and antagonist affinities. Themethod allows thecharacterization hormone). So far no small-molecule, selective SST5 receptor antagonists of the mode of binding, i.e. the contribution of differentparts of the anta- have been described. Therefore, receptorspecific antagonists are of high gonists to the overall affinity.The bindingwas determined through three interest as toolstostudy the diverse pharmacology of SST. In order to iden- methods, surface plasmon
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