Evaluation of amide replacements in CCR5 antagonists as a means to increase intrinsic permeability. Part 2: SAR optimization and pharmacokinetic profile of a homologous azacyle series.
Replacement of a secondary amide with a piperidine or azetidine moiety in a series of CCR5 antagonists led to the discovery of compounds with increased intrinsic permeability. This effort led to the identification of a potent CCR5 antagonist which exhibited an improved in vivo pharmacokinetic profile.
Wanner
Jutta
J
Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. jutta.wanner@roche.com
Chen
Lijing
L
Lemoine
Rémy C
RC
Kondru
Rama
R
Jekle
Andreas
A
Heilek
Gabrielle
G
deRosier
André
A
Ji
Changhua
C
Berry
Pamela W
PW
Rotstein
David M
DM
D000577:Amides / Q000737:chemistry*; D001372:Aza Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D013329:Structure-Activity Relationship
D000577:Amides; D001372:Aza Compounds; D065100:CCR5 Receptor Antagonists