| Autor: |
Bratton LD; Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor, MI 48105, USA., Auerbach B, Choi C, Dillon L, Hanselman JC, Larsen SD, Lu G, Olsen K, Pfefferkorn JA, Robertson A, Sekerke C, Trivedi BK, Unangst PC |
| Jazyk: |
angličtina |
| Zdroj: |
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2007 Aug 15; Vol. 15 (16), pp. 5576-89. Date of Electronic Publication: 2007 May 17. |
| DOI: |
10.1016/j.bmc.2007.05.031 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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