Direct Synthesis of <i>N</i>‑Alkyl Arylglycines by Organocatalytic Asymmetric Transfer Hydrogenation of <i>N</i>‑Alkyl Aryl Imino Esters

The organocatalytic asymmetric transfer hydrogenation of <i>N</i>-alkyl aryl imino esters for the direct synthesis of <i>N</i>-alkylated arylglycinate esters is reported. High yields and enantiomeric ratios were obtained, and tolerance to a diverse set of functional groups facilitated the preparation of more complex molecules as well as intermediates for active pharmaceuticals. A simple recycling protocol was developed for the Brønsted acid catalyst which could be reused through five cycles with no loss of activity or selectivity

Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC₂ Agonism and Glucose-Dependent Insulin Secretion

Agonists of vasoactive intestinal peptide receptor 2 (VPAC₂) stimulate glucose-dependent insulin secretion, making them attractive candidates for the treatment of hyperglycaemia and type-II diabetes. Vasoactive intestinal peptide (VIP) is an endogenous peptide hormone that potently agonizes VPAC₂. However, VIP has a short serum half-life and poor pharmacokinetics in vivo and is susceptible to proteolytic degradation, making its development as a therapeutic agent challenging. Here, we investigated two peptide cyclization strategies, lactamisation and olefin-metathesis stapling, and their effects on VPAC₂ agonism, peptide secondary structure, protease stability, and cell membrane permeability. VIP analogues showing significantly enhanced VPAC₂ agonist potency, glucose-dependent insulin secretion activity, and increased helical content were discovered; however, neither cyclization strategy appeared to effect proteolytic stability or cell permeability of the resulting peptides

Discovery of AZD2716: A Novel Secreted Phospholipase A₂ (sPLA₂) Inhibitor for the Treatment of Coronary Artery Disease

Expedited structure-based optimization of the initial fragment hit <b>1</b> led to the design of (<i>R</i>)-<b>7</b> (AZD2716) a novel, potent secreted phospholipase A₂ (sPLA₂) inhibitor with excellent preclinical pharmacokinetic properties across species, clear <i>in vivo</i> efficacy, and minimized safety risk. Based on accumulated profiling data, (<i>R</i>)-<b>7</b> was selected as a clinical candidate for the treatment of coronary artery disease

Design of Selective sPLA₂‑X Inhibitor (−)-2-{2-[Carbamoyl-6-(trifluoromethoxy)‑1<i>H</i>‑indol-1-yl]pyridine-2-yl}propanoic Acid

A lead generation campaign identified indole-based sPLA₂-X inhibitors with a promising selectivity profile against other sPLA₂ isoforms. Further optimization of sPLA₂ selectivity and metabolic stability resulted in the design of (−)-<b>17</b>, a novel, potent, and selective sPLA₂-X inhibitor with an exquisite pharmacokinetic profile characterized by high absorption and low clearance, and low toxicological risk. Compound (−)-<b>17</b> was tested in an ApoE^–/– murine model of atherosclerosis to evaluate the effect of reversible, pharmacological sPLA₂-X inhibition on atherosclerosis development. Despite being well tolerated and achieving adequate systemic exposure of mechanistic relevance, (−)-<b>17</b> did not significantly affect circulating lipid and lipoprotein biomarkers and had no effect on coronary function or histological markers of atherosclerosis

Discovery of a Series of Indole‑2 Carboxamides as Selective Secreted Phospholipase A₂ Type X (sPLA₂‑X) Inhibitors

In order to assess the potential of sPLA₂-X as a therapeutic target for atherosclerosis, novel sPLA₂ 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