Alkene carbonylation reactions are important for the production of value-added bulk and fine chemicals. Nowadays, all industrial carbonylation processes make use of highly toxic and flammable carbon monoxide. In fact, these properties impede the wider use of carbonylation reactions in industry and academia. Hence, performing carbonylations without the use of CO is highly desired and will contribute to the further advancement of sustainable chemistry. Although the use of carbon monoxide surrogates in alkene carbonylation reactions has been reported intermittently in the last 30 years, only recently has this area attracted significant interest. This Minireview summarizes carbonylation reactions of alkenes using different carbon monoxide surrogates.

Carbonylations of Alkenes with CO Surrogates

Sulfoximines from a Medicinal Chemist's Perspective: Physicochemical and in vitro Parameters Relevant for Drug Discovery.

Recent advances in the transition metal catalyzed carbonylation of alkynes, arenes and aryl halides using CO surrogates

Hepatitis C virus is a blood-borne infection and the leading cause of chronic liver disease (including cirrhosis and cancer) and liver transplantation. Since the identification of HCV in 1989, there has been an extensive effort to identify and improve treatment options. An important milestone was reached in 2011 with the approval of the first-generation HCV NS3/4A protease inhibitors. However, new therapies are needed to improve cure rates, shorten treatment duration, and improve tolerability. Here we summarize the extensive medicinal chemistry effort to develop novel P2 cyclopentane macrocyclic inhibitors guided by HCV NS3 protease assays, the cellular replicon system, structure-based design, and a panel of DMPK assays. The selection of compound 29 (simeprevir, TMC435) as clinical candidate was based on its excellent biological, PK, and safety pharmacology profile. Compound 29 has recently been approved for treatment of chronic HCV infection in combination with pegylated interferon-α and ribavirin in Jap...

Discovery and Development of Simeprevir (TMC435), a HCV NS3/4A Protease Inhibitor

Metal-catalyzed amidation

Phenylglycine as a novel P2 scaffold in hepatitis C virus NS3 protease inhibitors.

Synthesis of novel aryl and heteroaryl acyl sulfonimidamides via Pd-catalyzed carbonylation using a nongaseous precursor.

Evaluation of a diverse set of potential P1 carboxylic acid bioisosteres in hepatitis C virus NS3 protease inhibitors.

Herein we present the preclinical characterization of novel compounds containing the linear acyl sulfonimidamide functionality. Specifically, we studied the pK(a), lipophilicity, in vitro metabolic ...

Preclinical characterization of acyl sulfonimidamides: potential carboxylic acid bioisosteres with tunable properties.

Hepatitis C virus (HCV) has deceived researchers for seventeen years now and although the current therapy regimen has been optimized by the development of pegylated interferon-alpha and the addition of ribavirin, no new agent to treat HCV infected patients has yet reached the market. A new era is approaching the HCV research due to new developments for the propagation of the virus in a cell-based system, which may lead to new drug innovations. Efforts in the search of new treatments for HCV infected patients are either focused on direct antiviral drugs, targeting the structural components or enzymes encoded by the virus, or indirect antiviral drugs, targeting host cell components (immunomodulators etc.). An inspection of the drug pipeline for HCV reveals representatives from both classes and of different mechanisms of action. Among the direct acting antiviral agents, inhibitors of the NS3 protease, the NS5B polymerase, and the viral RNA are the most intensively explored. However, there is also on-going and promising preclinical research, in different stages, on other potential targets as the structural protein E2 (for cell-entry inhibitors), the NS3 helicase, the p7 ion-channel, and the multifunctional NS5A protein. The combat of HCV will certainly require a combination of drugs of different mechanisms in order to reduce the emergence of resistance. The latest developments in the discovery of agents to treat HCV are reviewed, with special focus on direct small-molecule antiviral drugs, from a medicinal chemistry perspective.

Anja Sandström

Papers

Phenylglycine as a novel P2 scaffold in hepatitis C virus NS3 protease inhibitors.

Synthesis of novel aryl and heteroaryl acyl sulfonimidamides via Pd-catalyzed carbonylation using a nongaseous precursor.

Evaluation of a diverse set of potential P1 carboxylic acid bioisosteres in hepatitis C virus NS3 protease inhibitors.

Preclinical characterization of acyl sulfonimidamides: potential carboxylic acid bioisosteres with tunable properties.

New developments in the discovery of agents to treat hepatitis C.