Discovery of Clinical Candidate GSK1842799 As a Selective S1P₁ Receptor Agonist (Prodrug) for Multiple Sclerosis

To develop effective oral treatment for multiple sclerosis (MS), we discovered a series of alkyl-substituted biaryl amino alcohols as selective S1P₁ modulators. One exemplar is (<i>S</i>)-2-amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)­phenyl)-1,3,4-thiadiazol-2-yl)­propan-1-ol (<b>10</b>, GSK1842799). Upon phosphorylation, the compound (<b>10</b>-P) showed subnanomole S1P₁ agonist activity with >1000× selectivity over S1P₃. The alcohol <b>10</b> demonstrated good oral bioavailability and rapid in vivo conversion to <b>10</b>-P. Dosed orally at 0.1 mg/kg, <b>10</b> significantly reduced blood lymphocyte counts 6 h postdose, and at 3 mg/kg, <b>10</b> achieved efficacy equivalent to FTY720 in the mouse EAE model of MS. Further pharmacokinetic/pharmacodynamic (PK/PD) study with cynomolgus monkeys indicated that, after oral dosing of <b>10</b> at 3.8 mg/kg, the active phosphate reached plasma levels that are comparable to FTY-720 phosphate (FTY-P) revealed in human clinical pharmacokinetics studies. On the basis of the favorable in vitro ADME and in vivo PK/PD properties as well as broad toxicology evaluations, compound <b>10</b> (GSK1842799) was selected as a candidate for further clinical development

Design and Application of a DNA-Encoded Macrocyclic Peptide Library

A DNA-encoded macrocyclic peptide library was designed and synthesized with 2.4 × 10¹² members composed of 4–20 natural and non-natural amino acids. Affinity-based selection was performed against two therapeutic targets, VHL and RSV N protein. On the basis of selection data, some peptides were selected for resynthesis without a DNA tag, and their activity was confirmed

Discovery of Thieno[3,2‑<i>d</i>]pyrimidine-6-carboxamides as Potent Inhibitors of SIRT1, SIRT2, and SIRT3

The sirtuins SIRT1, SIRT2, and SIRT3 are NAD⁺ dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic, and neurodegenerative disorders. Encoded library technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g., <b>11c</b>: IC₅₀ = 3.6, 2.7, and 4.0 nM for SIRT1, SIRT2, and SIRT3, respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogues <b>28</b> and <b>31</b>. Crystallographic studies of <b>11c</b>, <b>28</b>, and <b>31</b> bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors, which makes them valuable tools for sirtuin research

Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT)

In the search of PI3K p110α wild type and H1047R mutant selective small molecule leads, an encoded library technology (ELT) campaign against the desired target proteins was performed which led to the discovery of a selective chemotype for PI3K isoforms from a three-cycle DNA encoded library. An X-ray crystal structure of a representative inhibitor from this chemotype demonstrated a unique binding mode in the p110α protein

Discovery and Characterization of a Class of Pyrazole Inhibitors of Bacterial Undecaprenyl Pyrophosphate Synthase

Undecaprenyl pyrophosphate synthase (UppS) is an essential enzyme in bacterial cell wall synthesis. Here we report the discovery of <i>Staphylococcus aureus</i> UppS inhibitors from an Encoded Library Technology screen and demonstrate binding to the hydrophobic substrate site through cocrystallography studies. The use of bacterial strains with regulated <i>uppS</i> expression and inhibitor resistant mutant studies confirmed that the whole cell activity was the result of UppS inhibition, validating UppS as a druggable antibacterial target

Encoded Library Technology as a Source of Hits for the Discovery and Lead Optimization of a Potent and Selective Class of Bactericidal Direct Inhibitors of <i>Mycobacterium tuberculosis</i> InhA

Tuberculosis (TB) is one of the world’s oldest and deadliest diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase from <i>Mycobacterium tuberculosis</i>, is the target of the frontline antitubercular drug isoniazid (INH). Compounds that directly target InhA and do not require activation by mycobacterial catalase peroxidase KatG are promising candidates for treating infections caused by INH resistant strains. The application of the encoded library technology (ELT) to the discovery of direct InhA inhibitors yielded compound <b>7</b> endowed with good enzymatic potency but with low antitubercular potency. This work reports the hit identification, the selected strategy for potency optimization, the structure–activity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound <b>65</b>