Francois Bilodeau

• Boehringer Ingelheim

Establishing robust structure–activity relationships (SARs) is key to successful drug discovery campaigns, yet it often remains elusive due to screening and hit validation artifacts (false positives and false negatives), which frequently result in unproductive downstream expenditures of time and resources. To address this issue, we developed an int...

Fragment-based lead discovery has emerged over the last decades as one of the most powerful techniques for identifying starting chemical matter to target specific proteins or nucleic acids in vitro. However, the use of such low-molecular-weight fragment molecules in cell-based phenotypic assays has been historically avoided because of concerns that...

The Front Cover shows a macrophage being attacked by Leishmania parasites. Fortunately, fragment small‐molecule “Fragman” comes to the rescue by defeating the malicious parasites and thus saving the grateful macrophage. This illustrates that fragment‐based phenotypic lead discovery (FPLD) can serve as a rapid and practical strategy to generate lead...

Fragment-based screening represents a potential means for smaller institutions to meet the needs for identifying the seeds for future medications. Fragment-Based Lead Discovery (FBLD) is becoming a via- ble complement and alternative to traditional high-throughput screens for discovering the seeds of future drugs. FBLD involves the screening of lib...

Central to drug discovery is the correct characterization of the primary structures of compounds. In general, medicinal chemists make great synthetic and characterization efforts to deliver the intended compounds. However, there are occasions which incorrect compounds are presented, such as those reported for Bosutinib and TIC10. This may be due to...

Optimization of pyridine-based NCINIs based on compound 2 has led to the discovery of molecules capable of inhibiting virus harboring N124 variants of IN while maintaining minimal contribution of enterohepatic recirculation to clearance in rat. Structure-activity relationships at the C6 position established chemical space where the extent of entero...

A high-throughput screen based on a viral replication assay was used to identify inhibitors of the human cytomegalovirus. Using this approach, hit compound 1 was identified as a 4 μM inhibitor of HCMV that was specific and selective over other herpes viruses. Time of addition studies indicated compound 1 exerted its antiviral effect early in the vi...

A scaffold replacement approach was used to identifying the pyridine series of noncatalytic site integrase inhibitors. These molecules bind with higher affinity to a tetrameric form compared to a dimeric form of integrase. Optimization of the C6 and C4 positions revealed that viruses harboring T124 or A124 amino acid substitutions are highly suscep...

An assay recapitulating the 3′ processing activity of HIV-1 integrase (IN) was used to screen the Boehringer Ingelheim compound collection. Hit-to-lead and lead optimization beginning with compound 1 established the importance of the C3 and C4 substituent to antiviral potency against viruses with different aa124/aa125 variants of IN. The importance...

A classic synthetic issue that remains unresolved is the reaction that involves the control of N- versus O-alkylation of ambident anions. This common chemical transformation is important for medicinal chemists, who require predictable and reliable protocols for the rapid synthesis of inhibitors. The uncertainty of whether the product(s) are N- and/...

An electron-deficient, valine-derived triazolium salt is shown to catalyze a highly chemo- and enantioselective cross-benzoin reaction between aliphatic aldehydes and α-ketoesters. This methodology represents the first high yielding and highly enantioselective intermolecular cross-benzoin reaction using an organocatalyst (up to 94% ee). Further dia...

In this report we describe the synthesis and evaluation of diverse 4-arylproline analogs as HCV NS3 protease inhibitors. Introduction of this novel P2 moiety opened up new SAR and, in combination with a synthetic approach providing a versatile handle, allowed for efficient exploitation of this novel series of NS3 protease inhibitors. Multiple struc...

The use of β,γ-unsaturated-α-ketoesters in the intermolecular Stetter reaction furnishes 1,2,5-tricarbonyl compounds in high yield and excellent enantioselectivity. The α,δ-diketoesters generated using this methodology serve as useful synthetic building blocks via chemo- and diastereoselective transformations.

A very efficient NHC-catalyzed lactamization reaction is reported. For most cases, the ring expansion reaction proceeds to cleanly furnish five- and six-membered N-Ts and N-Bn lactams, without the need for further purification. Evidence is presented suggesting a dual role for the stoichiometric base: (1) deprotonation of the triazolium precatalyst...

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A full overview of the decarboxylative cross-coupling reaction between heteroaromatic carboxylic acids and aryl halides is described. This transformation employs palladium catalysts with short reaction times providing facile synthesis of aryl-substituted heteroaromatics. The effect of each reaction parameter including solvent, base, and additive em...

Aryl-substituted five-membered heteroaromatics have attracted great interest over the past years due to their presence in a large number of pharmaceuticals and natural products. Recently, an advance in the preparation of these scaffolds was achieved by employing a C-H functionalization strategy. This method allows easy access to these biaryl motifs...