Despite decades of ground-breaking research in academia, organic synthesis is still a rate-limiting factor in drug-discovery projects. Here we present some current challenges in synthetic organic chemistry from the perspective of the pharmaceutical industry and highlight problematic steps that, if overcome, would find extensive application in the discovery of transformational medicines. Significant synthesis challenges arise from the fact that drug molecules typically contain amines and N-heterocycles, as well as unprotected polar groups. There is also a need for new reactions that enable non-traditional disconnections, more C-H bond activation and late-stage functionalization, as well as stereoselectively substituted aliphatic heterocyclic ring synthesis, C-X or C-C bond formation. We also emphasize that syntheses compatible with biomacromolecules will find increasing use, while new technologies such as machine-assisted approaches and artificial intelligence for synthesis planning have the potential to dramatically accelerate the drug-discovery process. We believe that increasing collaboration between academic and industrial chemists is crucial to address the challenges outlined here.

Down syndrome (DS) is associated with neurological complications, including cognitive deficits that lead to impairment in intellectual

The data further support the potential of GABAA alpha5 receptors as a target for cognition-enhancing drugs. The dual binding and functional selectivity offers an ideal profile for cognition-enhancing effects without the unwanted side effects associated with activity at other GABAA receptor subtypes.

Background and purpose: As baclofen is active in patients with anxiety disorders, GABA B receptors have been implicated in the modulation of anxiety. To avoid the side effects of baclofen, allosteric enhancers of GABA B receptors have been studied to provide an alternative therapeutic avenue for modulation of GABA B receptors. The aim of this study was to characterize derivatives of (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) as enhancers of GABA B receptors. Experimental approach: Enhancing properties of rac-BHFF were assessed in the Chinese hamster ovary (CHO)-Ga16-hGABA B(1a,2a) cells by Fluorometric Imaging Plate Reader and GTPg[35 S]-binding assays, and in rat hippocampal slices by population spike (PS) recordings. In vivo activities of rac-BHFF were assessed using the loss of righting reflex (LRR) and stressinduced hyperthermia (SIH) models. Key results: In GTPg[35 S]-binding assays, 0.3 mM rac-BHFF or its pure enantiomer ( þ )-BHFF shifted the GABA concentrationresponse curve to the left, an effect that resulted in a large increase in both GABA potency (by 15.3-and 87.3-fold) and efficacy (149% and 181%), respectively. In hippocampal slices, rac-BHFF enhanced baclofen-induced inhibition of PS of CA1 pyramidal cells. In an in vivo mechanism-based model in mice, rac-BHFF increased dose-dependently the LRR induced by baclofen with a minimum effective dose of 3 mg kg À1 p.o. rac-BHFF (100 mg kg À1 p.o.) tested alone had no effect on LRR nor on spontaneous locomotor activity, but exhibited anxiolytic-like activity in the SIH model in mice. Conclusions and implications: rac-BHFF derivatives may serve as valuable pharmacological tools to elucidate the pathophysiological roles played by GABA B receptors in the central and peripheral nervous systems.

Kupfer‐vermittelte C(Aryl)‐N‐, C(Aryl)‐O‐ und C(Aryl)‐S‐ Verknüpfungen sind Kupplungsreaktionen mit einer großen Bandbreite an Substraten. In dieser Hinsicht ergänzt diese Methode die Palladium‐vermittelten Arylierungsreaktionen. Hier beschreiben wir neue Entwicklungen bei stöchiometrischen und katalytischen Varianten der Reaktionen mit Arylboronsäuren, Arylhalogeniden, Iodoniumsalzen, Siloxanen, Stannanen, Plumbanen, Bismutaten und Trifluoroboraten als Aryldonoren. Erst kürzlich wurden Arylboronsäuren als Reaktionspartner für die O‐ und N‐Arylierung eingeführt; dieser Klasse von Aryldonoren wird in diesem Aufsatz besondere Aufmerksamkeit gewidmet. Durch die Verwendung unterschiedlicher Kupferquellen und Basen sowie zusätzlicher Liganden und Additive konnten deutliche Verbesserungen erzielt werden. Mechanistische Untersuchungen sollen Aufschluss über die katalytisch aktiven Spezies geben und so zur Entwicklung milderer Methoden mit größerer Effizienz führen. Der Aufsatz umfasst die Literatur bis Ende April 2003.