Synthesis of [(3) H] and [(2) H6 ]AZD6642, an inhibitor of 5-lipoxygenase activating protein (FLAP).
An AstraZeneca effort to identify a 5-lipoxygenase activating protein inhibitor with good drug-like properties resulted in the identification of AZD6642. To further understand its drug metabolism and pharmacokinetic properties, it was required labeled with tritium. The tritiation of AZD6642 was effected by Ir-catalyzed exchange chemistry to give an average of one tritium per molecule. Additionally, a stable isotope labeled version of AZD6642 was required to support bioanalytical studies. The synthesis originated from [(2) H6 ]acetone which was converted to the trimethylsilyl cyanide adduct and subsequently reduced to give 2-(aminomethyl)-[1,1,1,3,3,3-(2) H6 ]propan-2-ol in good yield. Carbonylation to give an amide adduct resulted in an intermediate that was converted to the final compound in four steps.
Isotope Chemistry, Enabling Services, Drug Safety and Metabolism iMED, AstraZeneca Pharmaceuticals LP, Mölndal, Sweden.
Åsa
Å
Lindelöf
Isotope Chemistry, Enabling Services, Drug Safety and Metabolism iMED, AstraZeneca Pharmaceuticals LP, Mölndal, Sweden.
Cecilia
C
Ericsson
Isotope Chemistry, Enabling Services, Drug Safety and Metabolism iMED, AstraZeneca Pharmaceuticals LP, Mölndal, Sweden.
Roger
R
Simonsson
Isotope Chemistry, Enabling Services, Drug Safety and Metabolism iMED, AstraZeneca Pharmaceuticals LP, Mölndal, Sweden.
Göran
G
Nilsson
Structure Analysis & Separation Science, Medicinal Chemistry, Respiratory, Inflammation, and Autoimmune iMED, AstraZeneca Pharmaceuticals LP, Mölndal, Sweden.
Gunnar
G
Grönberg
Isotope Chemistry, Enabling Services, Drug Safety and Metabolism iMED, AstraZeneca Pharmaceuticals LP, Mölndal, Sweden.
Charles S
CS
Elmore
D058946:5-Lipoxygenase-Activating Protein Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058927:5-Lipoxygenase-Activating Proteins / Q000378:metabolism*; D000096:Acetone / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic; D007553:Isotope Labeling; D010848:Picolinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014316:Tritium / Q000737:chemistry*
C000596370:5-(2-(4-(5-aminopyrazin-2-yl)phenyl)tetrahydrofuran-2-yl)-N-(2-hydroxy-2-methylpropyl)pyridine-2-carboxamide; D058946:5-Lipoxygenase-Activating Protein Inhibitors; D058927:5-Lipoxygenase-Activating Proteins; D010848:Picolinic Acids; D011719:Pyrazines; D014316:Tritium; D000096:Acetone
3H; 5-lipoxygenase activating protein; AZD6642; Ir; hydrogen-isotope exchange