Discovery and Early Clinical Development of an Inhibitor of 5-Lipoxygenase Activating Protein (AZD5718) for Treatment of Coronary Artery Disease.

5-Lipoxygenase activating protein (FLAP) inhibitors attenuate 5-lipoxygenase pathway activity and reduce the production of proinflammatory and vasoactive leukotrienes. As such, they are hypothesized to have therapeutic benefit for the treatment of diseases that involve chronic inflammation including coronary artery disease. Herein, we disclose the medicinal chemistry discovery and the early clinical development of the FLAP inhibitor AZD5718 (12).

Design of Selective sPLA-X Inhibitor (-)-2-{2-[Carbamoyl-6-(trifluoromethoxy)-1-indol-1-yl]pyridine-2-yl}propanoic Acid.

A lead generation campaign identified indole-based sPLA-X inhibitors with a promising selectivity profile against other sPLA isoforms. Further optimization of sPLA selectivity and metabolic stability resulted in the design of (-)-, a novel, potent, and selective sPLA-X inhibitor with an exquisite pharmacokinetic profile characterized by high absorption and low clearance, and low toxicological risk. Compound (-)- was tested in an ApoE murine model of atherosclerosis to evaluate the effect of reversible, pharmacological sPLA-X inhibition on atherosclerosis development.

Discovery of a Series of Indole-2 Carboxamides as Selective Secreted Phospholipase A Type X (sPLA-X) Inhibitors.

In order to assess the potential of sPLA-X as a therapeutic target for atherosclerosis, novel sPLA inhibitors with improved type X selectivity are required. To achieve the objective of identifying such compounds, we embarked on a lead generation effort that resulted in the identification of a novel series of indole-2-carboxamides as selective sPLA2-X inhibitors with excellent potential for further optimization.

Small molecule modulators of PCSK9 - A literature and patent overview.

Proprotein convertase subtilisin kexin like type 9 (PCSK9) has since its discovery been a key protein target for the modulation of LDL cholesterol. The interest in PCSK9 has grown even more with the positive clinical trial outcomes in cardiovascular disease recently reported for two PCSK9 antibodies. Currently, there are no PCSK9 small molecule programs active in clinical development.

Discovery of AZD2716: A Novel Secreted Phospholipase A (sPLA) Inhibitor for the Treatment of Coronary Artery Disease.

Expedited structure-based optimization of the initial fragment hit led to the design of ()- (AZD2716) a novel, potent secreted phospholipase A (sPLA) inhibitor with excellent preclinical pharmacokinetic properties across species, clear efficacy, and minimized safety risk. Based on accumulated profiling data, ()- was selected as a clinical candidate for the treatment of coronary artery disease.

Recent advances for FLAP inhibitors.

A number of FLAP inhibitors have been progressed to clinical trials for respiratory and other inflammatory indications but so far no drug has reached the market. With this Digest we assess the opportunity to develop FLAP inhibitors for indications beyond respiratory disease, and in particular for atherosclerotic cardiovascular disease. We also show how recently disclosed FLAP inhibitors have structurally evolved from the first generation FLAP inhibitors paving the way for new compound classes.

Discovery of the Fibrinolysis Inhibitor AZD6564, Acting via Interference of a Protein-Protein Interaction.

A class of novel oral fibrinolysis inhibitors has been discovered, which are lysine mimetics containing an isoxazolone as a carboxylic acid isostere. As evidenced by X-ray crystallography the inhibitors bind to the lysine binding site in plasmin thus preventing plasmin from binding to fibrin, hence blocking the protein-protein interaction. Optimization of the series, focusing on potency in human buffer and plasma clotlysis assays, permeability, and GABAa selectivity, led to the discovery of AZD6564 (19) displaying an in vitro human plasma clot lysis IC50 of 0.

An easy entry to optically active alpha-amino phosphonic acid derivatives using phase-transfer catalysis (PTC).

The unprecedented use of phase-transfer catalysis (PTC) in an asymmetric hydrophosphonylation reaction allows the obtainment of a range of optically active alpha-amino phosphonic acid derivatives directly from alpha-amido sulfones.

Organocatalytic asymmetric Mannich reactions with N-Boc and N-Cbz protected alpha-amido sulfones (Boc: tert-butoxycarbonyl, Cbz: benzyloxycarbonyl).

Different malonates and beta-ketoesters can react with N-tert-butoxycarbonyl- (N-Boc) and N-benzyloxycarbonyl- (N-Cbz) protected alpha-amido sulfones in an organocatalytic asymmetric Mannich-type reaction. The reaction makes use of a simple and easily obtained phase-transfer catalyst and proceeds under very mild and user-friendly conditions. The optimised protocol avoids the preparation and the isolation of the relatively unstable N-Boc and N-Cbz imines that are generated in situ from the bench-stable alpha-amido sulfones.

Phase transfer catalyzed enantioselective Strecker reactions of alpha-amido sulfones with cyanohydrins.

A study into the use of a chiral phase-transfer catalyst in conjunction with acetone cyanohydrin to effect the enantioselective formation of alpha-amino nitriles from alpha-amido sulfones is described. This novel catalytic asymmetric Strecker reaction is analyzed with regard to the possible mechanistic basis.

Direct access to enantiomerically enriched alpha-amino phosphonic acid derivatives by organocatalytic asymmetric hydrophosphonylation of imines.

A simple and efficient organocatalytic enantioselective hydrophosphonylation of imines to enantiomerically enriched alpha-amino phosphonates is reported. By using 10 mol % of quinine as the catalyst in the enantioselective addition of diethyl phosphite to N-Boc protected imines, alpha-amino phosphonates are obtained in moderate to good yields and with up to 94% ee.