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Four diastereomers of the biosynthetic substrate for module 2 of the rifamycin polyketide synthase (PKS) in form of their N-acetylcysteamine (SNAC) thioesther are synthesized. Only one diastereomer was turned over in vivo into rifamycin B, thus establishing the obscured absolute and relative configuration of the native biosynthetic intermediates.

The Hit to Lead (H2L) process is an integral part of contemporary drug discovery, encompassing the optimisation of validated Hit structures into Lead molecules. High quality leads build confidence, through activity and property profiles as well as preliminary biological data, which might include validating pharmacologic hypotheses along the way, indicating that further investment in the structure(s) and target would be worthwhile. Leads have line of sight to a development candidate and bring an understanding of what priorities Lead Optimisation should address. In this set of best practices, we detail the essential criteria that characterise a good lead, which include establishing SAR from analogues and assessing preliminary DMPK indicators, selectivity and early safety parameters. We highlight the importance of identifying liabilities of the lead series and demonstrating that each can be individually modulated whilst maintaining on target potency. We make the case for having physicochemical properties as critical optimisation parameters and how ligand efficiency metrics can enable this. Then we go over general tactics that can be used to convert hits into a lead series. These include essential steps that, when performed early, increase the chance of success such as deconstructive SAR, pharmacophore and bioactive conformation determination and scaffold optimisation. Finally, we suggest decision-making criteria to substantiate confidence in further investment or, as importantly, making a recommendation to cease further work on a series., (© 2025 Wiley-VCH GmbH.)

The 17 th EFMC Short Course on Medicinal Chemistry took place April 23-26, 2023 in Oegstgeest, near Leiden in the Netherlands. It covered for the first time the exciting topic of Targeted Protein Degradation (full title: Small Molecule Protein Degraders: A New Opportunity for Drug Design and Development). The course was oversubscribed, with 35 attendees and 6 instructors mainly from Europe but also from the US and South Africa, and representing both industry and academia. This report summarizes the successful event, key lectures given and topics discussed., (© 2023 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Herein, we describe the identification, chemical optimization, and preclinical characterization of novel soluble guanylate cyclase (sGC) stimulators. Given the very broad therapeutic opportunities for sGC stimulators, new tailored molecules for distinct indications with specific pharmacokinetics, tissue distribution, and physicochemical properties will be required in the future. Here, we report the ultrahigh-throughput (uHTS)-based discovery of a new class of sGC stimulators from an imidazo[1,2- a ]pyridine lead series. Through the extensive and staggered optimization of the initial screening hit, liabilities such as potency, metabolic stability, permeation, and solubility could be substantially improved in parallel. These efforts resulted ultimately in the discovery of the new sGC stimulators 22 and 28 . It turned out that BAY 1165747 (BAY-747, 28 ) could be an ideal treatment alternative for patients with hypertension, especially those not responding to standard anti-hypertensive therapy (resistant hypertension). BAY-747 ( 28 ) demonstrated sustained hemodynamic effects up to 24 h in phase 1 studies.

The development and design of reliable and efficient methods for the construction of chiral building blocks are crucial in modern natural product synthesis. 8-Oxabicyclo[3.2.1]oct-6-en-3-ones are readily accessible scaffolds with defined stereochemical features which have been exploited for non-aldol approaches to the preparation of chiral building blocks. Strategies for their enantioselective synthesis, including asymmetric cycloaddition methods, desymmetrization protocols, and "racemic switch operations", are presented and evaluated.