Novel hexahydropyrrolo[3,4-c]pyrrole CCR5 antagonists.
Starting with a high-throughput screening lead, a novel series of CCR5 antagonists was developed utilizing an information-based approach. Improvement of pharmacokinetic properties for the series was pursued by SAR exploration of the lead template. The synthesis, SAR and biological profiles of the series are described.
Rotstein
David M
DM
Roche Palo Alto LLC, Palo Alto, CA 94304, USA. david.rotstein@comcast.net
Melville
Chris R
CR
Padilla
Fernando
F
Cournoyer
Dick
D
Lee
Eun K
EK
Lemoine
Remy
R
Petersen
Ann C
AC
Setti
Lina Q
LQ
Wanner
Jutta
J
Chen
Lijing
L
Filonova
Lubov
L
Loughhead
David G
DG
Manka
Jason
J
Lin
Xiao-Fa
XF
Gleason
Shelley
S
Sankuratri
Surya
S
Ji
Changhua
C
Derosier
Andre
A
Dioszegi
Marianna
M
Heilek
Gabrielle
G
Jekle
Andreas
A
Berry
Pamela
P
Mau
Cheng-I
CI
Weller
Paul
P
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D019713:Receptors, CCR5 / Q000378:metabolism; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D001549:Benzamides; D065100:CCR5 Receptor Antagonists; D023581:HIV Fusion Inhibitors; D011758:Pyrroles; D019713:Receptors, CCR5