Development of a Multi-Kilogram-Scale Synthesis of AZD1283: A Selective and Reversible Antagonist of the P2Y₁₂ Receptor

Ethyl 6-chloro-5-cyano-2-methylnicotinate (<b>4</b>) was coupled with 4-piperidinecarboxylic acid (isonipecotic acid) in 81% yield to pyridine acid <b>10</b>. An amide coupling between <b>10</b> and benzylsulfonamide (<b>6</b>) afforded AZD1283 (<b>1</b>) in 79% yield using CDI as coupling reagent. The synthesis has been developed and scaled up to 20 kg batches of <b>1</b>, supporting preclinical and clinical studies. Development work towards 2-chloropyridine <b>4</b> and benzylsulfonamide (<b>6</b>) is included

Lead Optimization of Ethyl 6‑Aminonicotinate Acyl Sulfonamides as Antagonists of the P2Y₁₂ Receptor. Separation of the Antithrombotic Effect and Bleeding for Candidate Drug AZD1283

Synthesis and structure–activity relationships of ethyl 6-aminonicotinate acyl sulfonamides, which are potent antagonists of the P2Y₁₂ receptor, are presented. Shifting from 5-chlorothienyl to benzyl sulfonamides significantly increased the potency in the residual platelet count assay. Evaluation of PK parameters in vivo in dog for six compounds showed a 10-fold higher clearance for the azetidines than for the matched-pair piperidines. In a modified Folts model in dog, both piperidine <b>3</b> and azetidine <b>13</b> dose-dependently induced increases in blood flow and inhibition of ADP-induced platelet aggregation with antithrombotic ED₅₀ values of 3.0 and 10 μg/kg/min, respectively. The doses that induced a larger than 3-fold increase in bleeding time were 33 and 100 μg/kg/min for <b>3</b> and <b>13</b>, respectively. Thus, the therapeutic index (TI) was ≥10 for both compounds. On the basis of these data, compound <b>3</b> was progressed into human clinical trials as candidate drug AZD1283

Systematic Tuning of Fluoro-galectin‑3 Interactions Provides Thiodigalactoside Derivatives with Single-Digit nM Affinity and High Selectivity

Symmetrical and asymmetrical fluorinated phenyltriazolyl-thiodigalactoside derivatives have been synthesized and evaluated as inhibitors of galectin-1 and galectin-3. Systematic tuning of the phenyltriazolyl-thiodigalactosides’ fluoro-interactions with galectin-3 led to the discovery of inhibitors with exceptional affinities (<i>K</i>_d down to 1–2 nM) in symmetrically substituted thiodigalactosides as well as unsurpassed combination of high affinity (<i>K</i>_d 7.5 nM) and selectivity (46-fold) over galectin-1 for asymmetrical thiodigalactosides by carrying one trifluorphenyltriazole and one coumaryl moiety. Studies of the inhibitor–galectin complexes with isothermal titration calorimetry and X-ray crystallography revealed the importance of fluoro-amide interaction for affinity and for selectivity. Finally, the high affinity of the discovered inhibitors required two competitive titration assay tools to be developed: a new high affinity fluorescent probe for competitive fluorescent polarization and a competitive ligand optimal for analyzing high affinity galectin-3 inhibitors with competitive isothermal titration calorimetry