Design and synthesis of pyridin-2-ylmethylaminopiperidin-1-ylbutyl amide CCR5 antagonists that are potent inhibitors of M-tropic (R5) HIV-1 replication.
A series of CCR5 antagonists were optimized for potent inhibition of R5 HIV-1 replication in peripheral blood mononuclear cells. Compounds that met acceptable ADME criteria, selectivity, human plasma protein binding, potency shift in the presence of α-glycoprotein were evaluated in rat and dog pharmacokinetics.
Genzyme Corp., 153 Second Avenue, Waltham, MA 02451, USA. renato.skerlj@genzyme.com
Renato
R
Skerlj
Gary
G
Bridger
Yuanxi
Y
Zhou
Elyse
E
Bourque
Ernest
E
McEachern
Jonathan
J
Langille
Curtis
C
Harwig
Duane
D
Veale
Wen
W
Yang
Tongshong
T
Li
Yongbao
Y
Zhu
Michael
M
Bey
Ian
I
Baird
Michael
M
Sartori
Markus
M
Metz
Renee
R
Mosi
Kim
K
Nelson
Veronique
V
Bodart
Rebecca
R
Wong
Simon
S
Fricker
Ron
R
Mac Farland
Dana
D
Huskens
Dominique
D
Schols
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D004285:Dogs; D015195:Drug Design; D015497:HIV-1; D006801:Humans; D020128:Inhibitory Concentration 50; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D014779:Virus Replication / Q000187:drug effects
D000577:Amides; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D010880:Piperidines; D011725:Pyridines