3 research outputs found
Development of a Multi-Kilogram-Scale Synthesis of AZD1283: A Selective and Reversible Antagonist of the P2Y<sub>12</sub> 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 P2Y<sub>12</sub> 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 P2Y<sub>12</sub> 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 ED<sub>50</sub> 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><sub>d</sub> down to
1–2 nM) in symmetrically substituted thiodigalactosides as
well as unsurpassed combination of high affinity (<i>K</i><sub>d</sub> 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