CCR5 antagonists: 3-(pyrrolidin-1-yl)propionic acid analogues with potent anti-HIV activity.
[reaction: see text] A novel approach to alpha,alpha-disubstituted-beta-amino acids (beta(2,2)-amino acids) was employed in the synthesis of a series of 3-(pyrrolidin-1-yl)propionic acids possessing high affinity for the CCR5 receptor and potent anti-HIV activity. The rat pharmacokinetics for these new analogues featured higher bioavailabilities and lower rates of clearance as compared to cyclopentane 1.
Lynch
Christopher L
CL
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA. christopher.lynch@abbott.com
Hale
Jeffrey J
JJ
Budhu
Richard J
RJ
Gentry
Amy L
AL
Finke
Paul E
PE
Caldwell
Charles G
CG
Mills
Sander G
SG
MacCoss
Malcolm
M
Shen
Dong-Ming
DM
Chapman
Kevin T
KT
Malkowitz
Lorraine
L
Springer
Martin S
MS
Gould
Sandra L
SL
DeMartino
Julie A
JA
Siciliano
Salvatore J
SJ
Cascieri
Margaret A
MA
Carella
Anthony
A
Carver
Gwen
G
Holmes
Karen
K
Schleif
William A
WA
Danzeisen
Renee
R
Hazuda
Daria
D
Kessler
Joseph
J
Lineberger
Janet
J
Miller
Michael
M
Emini
Emilio
E
D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D065100:CCR5 Receptor Antagonists; D011422:Propionates / Q000493:pharmacokinetics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000493:pharmacokinetics / Q000494:pharmacology*
C478986:3-(pyrrolidin-1-yl)propionic acid; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D011422:Propionates; D011759:Pyrrolidines