29.03.2013 Views

MEDICINAL CHEMISTRY

MEDICINAL CHEMISTRY

MEDICINAL CHEMISTRY

SHOW MORE
SHOW LESS

You also want an ePaper? Increase the reach of your titles

YUMPU automatically turns print PDFs into web optimized ePapers that Google loves.

Structure-activity Relationship<br />

Mevastatin and lovastatin served as lead compounds in the development of additional<br />

HMGRIS. The lactone and bicyclic rings as well as the ethylene bridge between them<br />

responsible for the activity of HMGRIs. Additionally, it was found that the bicyclic ring<br />

could be replaced with other lipophilic rings and that the size and shape of these other<br />

ring systems were important to the overall activity of the compounds. Minor<br />

modifications of the bicyclic ring and side chain ester of lovastatin produced simvastatin<br />

and pravastatin . Pravastatin, a ring-opened dihydroxyacid with a 6'-hydroxyl group, is<br />

much more hydrophilic than either lovastatin or simvastatin. Proposed advantages of this<br />

enhanced hydrophilicity are minimal penetration into the lipophilic membranes of<br />

peripheral cells, better selectivity for hepatic tissues, and a reduction in the incidence of<br />

side effects seen with lovastatin and simvastatin.<br />

The initial rationale centered on a desire to simplify the structures of mevastatin and<br />

lovastatin. The 2, 4-dichlorophenyl analog (compound 181) shown below was one of the<br />

first cornpounds to demonstrate that this type of substitution was possible. The<br />

replacement of the bicyclic ring with various substituted, aromatic ring systems led to the<br />

development of fluvastatin (180), atorvastatin (182), and cerivastatin.<br />

Cl<br />

HO<br />

Cl<br />

Compound (181)<br />

O<br />

H<br />

O<br />

F<br />

HO<br />

N<br />

O<br />

Atrovastatin (182)<br />

H<br />

CO 2Na<br />

However, compound (181) was considerably less potent than mevastatin. Subsequent<br />

research investigated a variety of aromatic substitutions and heterocyclic ring systems in<br />

order to optimize HMGRI activity. The substituted pyrrole (compound 183) shown below<br />

retained 30% of the activity of mevastatin and was a key intermediate in the substitutions<br />

and the addition of spacer groups, have produced a number of active compounds.<br />

F<br />

HO<br />

N<br />

Compound (183)<br />

H<br />

O<br />

O<br />

OH<br />

NH

Hooray! Your file is uploaded and ready to be published.

Saved successfully!

Ooh no, something went wrong!