Design and synthesis of hepatoselective, pyrrole-based HMG-CoA reductase inhibitors.
This manuscript describes the design and synthesis of a series of pyrrole-based inhibitors of HMG-CoA reductase for the treatment of hypercholesterolemia. Analogs were optimized using structure-based design and physical property considerations resulting in the identification of 44, a hepatoselective HMG-CoA reductase inhibitor with excellent acute and chronic efficacy in a pre-clinical animal models.
Pfefferkorn
Jeffrey A
JA
Pfizer Global Research & Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. jeffrey.a.pfefferkorn@pfizer.com
Song
Yuntao
Y
Sun
Kuai-Lin
KL
Miller
Steven R
SR
Trivedi
Bharat K
BK
Choi
Chulho
C
Sorenson
Roderick J
RJ
Bratton
Larry D
LD
Unangst
Paul C
PC
Larsen
Scott D
SD
Poel
Toni-Jo
TJ
Cheng
Xue-Min
XM
Lee
Chitase
C
Erasga
Noe
N
Auerbach
Bruce
B
Askew
Valerie
V
Dillon
Lisa
L
Hanselman
Jeffrey C
JC
Lin
Zhiwu
Z
Lu
Gina
G
Robertson
Andrew
A
Olsen
Karl
K
Mertz
Thomas
T
Sekerke
Catherine
C
Pavlovsky
Alexander
A
Harris
Melissa S
MS
Bainbridge
Graeme
G
Caspers
Nicole
N
Chen
Huifen
H
Eberstadt
Matthias
M
D000818:Animals; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006949:Hyperlipidemias / Q000188:drug therapy; D008099:Liver / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*; D000068718:Rosuvastatin Calcium; D013329:Structure-Activity Relationship; D013449:Sulfonamides
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium