Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 2: Discovery of potent, selective, and orally bioavailable compounds.
Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound 1 afforded the isopropyl compound 9. This compound is a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1, an excellent selectivity profile, and good oral bioavailability in three animal species. During this investigation, a new method for the preparation of alpha-(pyrrolidin-1-yl)-alpha,alpha-dialkyl acetic acid from a pyrrolidine and alpha-bromo-alpha,alpha-dialkyl acetic acid using silver triflate was discovered. This allowed us to prepare compounds such as 24 and 25 for the first time. A novel Pd-mediated N-dealkylation of alpha-(pyrrolidin-1-yl)acetic acid was also uncovered.
Shen
Dong-Ming
DM
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. dongming_shen@merck.com
Shu
Min
M
Willoughby
Christopher A
CA
Shah
Shrenik
S
Lynch
Christopher L
CL
Hale
Jeffrey J
JJ
Mills
Sander G
SG
Chapman
Kevin T
KT
Malkowitz
Lorraine
L
Springer
Martin S
MS
Gould
Sandra L
SL
DeMartino
Julie A
JA
Siciliano
Salvatore J
SJ
Lyons
Kathy
K
Pivnichny
James V
JV
Kwei
Gloria Y
GY
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 D
MD
Emini
Emilio A
EA
D000085:Acetates / Q000737:chemistry / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D065100:CCR5 Receptor Antagonists; D004285:Dogs; D006367:HeLa Cells; D006801:Humans; D008253:Macaca mulatta; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship
D000085:Acetates; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D010880:Piperidines; D011720:Pyrazoles