Discovery of pyrrole-based hepatoselective ligands as potent inhibitors of HMG-CoA reductase.
In an effort to identify hepatoselective inhibitors of HMG-CoA reductase, two series of pyrroles were synthesized and evaluated. Efforts were made to modify (3R,5R)-7-[3-(4-fluorophenyl)-1-isopropyl-4-phenyl-5-phenylcarbamoyl-1H-pyrrol-2-yl]-3,5-dihydroxy-heptanoic acid sodium salt 30 in order to reduce its lipophilicity and therefore increase hepatoselectivity. Two strategies that were explored were replacement of the lipophilic 3-phenyl substituent with either a polar function (pyridyl series) or with lower alkyl substituents (lower alkyl series) and attachment of additional polar moieties at the 2-position of the pyrrole ring. One compound was identified to be both highly hepatoselective and active in vivo. We report the discovery, synthesis, and optimization of substituted pyrrole-based hepatoselective ligands as potent inhibitors of HMG-CoA reductase for reducing low density lipoprotein cholesterol (LDL-c) in the treatment of hypercholesterolemia.
Bratton
Larry D
LD
Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor, MI 48105, USA.
Auerbach
Bruce
B
Choi
Chulho
C
Dillon
Lisa
L
Hanselman
Jeffrey C
JC
Larsen
Scott D
SD
Lu
Gina
G
Olsen
Karl
K
Pfefferkorn
Jeffrey A
JA
Robertson
Andrew
A
Sekerke
Catherine
C
Trivedi
Bharat K
BK
Unangst
Paul C
PC
D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008024:Ligands; D011758:Pyrroles; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases