Diverse modifications of the 4-methylphenyl moiety of TAK-779 by late-stage Suzuki-Miyaura cross-coupling.
Chemokine receptor 5 (CCR5) antagonists provide a new therapeutic approach in the treatment of HIV-1 (AIDS). TAK-779 displays high affinity and selectivity for the CCR5 receptor and serves as a lead compound for the development of further antagonists. In order to increase the oral bioavailability replacement of the quaternary ammonium structure by a tertiary amine and modification of the 4-methylphenyl moiety were envisaged. Herein, a new synthetic strategy for the development of TAK-779 analogs by late stage diversification is reported. The Suzuki-Miyaura cross-coupling reactions allowed various modifications of the central amide building block 3 at the end of the synthesis leading to compounds 2f and 2h with a promising CCR5 binding affinity.
Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstr. 48, D-48149 Münster, Germany. wuensch@uni-muenster.de.
Anna
A
Junker
Dirk
D
Schepmann
Junichiro
J
Yamaguchi
Kenichiro
K
Itami
Andreas
A
Faust
Klaus
K
Kopka
Stefan
S
Wagner
Bernhard
B
Wünsch
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000577:Amides; D065100:CCR5 Receptor Antagonists; D000644:Quaternary Ammonium Compounds; C119369:TAK 779