Evaluation of secondary amide replacements in a series of CCR5 antagonists as a means to increase intrinsic membrane permeability. Part 1: Optimization of gem-disubstituted azacycles.
Replacement of a secondary amide with an N-acyl or N-sulfonyl gem-disubstituted azacyle in a series of CCR5 antagonists led to the identification of compounds with excellent in vitro HIV antiviral activity and increased intrinsic membrane permeability.
Lemoine
Rémy C
RC
Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. remy.lemoine@roche.com
Petersen
Ann C
AC
Setti
Lina
L
Wanner
Jutta
J
Jekle
Andreas
A
Heilek
Gabrielle
G
deRosier
André
A
Ji
Changhua
C
Berry
Pamela
P
Rotstein
David
D
D000577:Amides / Q000737:chemistry*; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D019713:Receptors, CCR5 / Q000378:metabolism
D000577:Amides; D019380:Anti-HIV Agents; D001372:Aza Compounds; D065100:CCR5 Receptor Antagonists; D023581:HIV Fusion Inhibitors; D019713:Receptors, CCR5