Chemistry Reference
In-Depth Information
led to the isolation (from
Aspergillus terreus
) and characterization of mevino-
lin (lovastatin
100
), which is a homolo of compactin (
101
) that was discovered
earlier (137, 138). These compounds possess a lipophilic hexahydrodecalin, a
2-methylbutanoate side chain, and a
-lactone connected to the decalin
unit with a two-carbon linker. These compounds are potent inhibitors of HMG
CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis, and inhibit
the synthesis of cholesterol in the liver. Lovastatin (Mevacor
®
) Merck & Co.,
Inc., Whitehouse Station, NJ; was the first compound approved for lowering
cholesterol in humans and became the cornerstone of all cholesterol-lowering
agents generically called “statins.” The modification of 2-methylbutanoate to
2,2-dimethylbutanoate led to the semisynthetic derivative, simvastatin (Zocor
®
,
Merck & Co., Inc., Whitehouse Station, NJ;
102
), the second and more effective
agent approved for human use (139). Hydroxylation of compactin by biotransfor-
mation led to pravastatin (Pravachol
®
,BMS,NY
103
) (139). The key pharma-
cophore of the statins is the
β
-hydroxy-
δ
-lactone or open acid. As the importance
and value of cholesterol lowering to human pathophysiology became clearer, the
search for additional cholesterol-lowering agents became more prominent and led
to the discovery and development of several other clinical agents. All these com-
pounds retained nature's gift of the pharmacophore,
β
-hydroxy-
δ
-lactone (or open
acid), with replacement of the decalin unit of the natural products with a variety
of aromatic lipophilic groups that resulted in fluvastin (
104
) (140), Atorvastatin
(
105
) (141), Cerivastatin (
106
, withdrawn from the clinic) (142), Rosuvastatin
(
107
) (143), and Pitavastatin (
108
). The statins have had tremendous impact in
improvement of overall human health and quality of life because of the lower-
ing of low-density lipoprotein (LDL) particles, which leads to a reduction in the
incidence of coronary heart disease; arguably, they are the most successful class
of medicines.
Ephedrine (
109
), isolated from the Chinese plant
Ephedra sinaica
,was
approved as one of the first bronchodilators and cardiovascular agents. This dis-
covery led to a variety of such antihypertensive agents including
β
-blockers (4).
Angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin
II, and its inhibition has led to several very successful, clinically useful antihy-
pertensive agents. Although these inhibitors are of synthetic origin, the original
lead was modeled after a nonapeptide, teprotide (
110
). This peptide was isolated
from snake (viper,
Bothrops jararaca
) venom by Ondetti et al. It had antihyper-
tensive activity in the clinic by parenteral administration (138, 144, 145) but was
devoid of oral activity. Ondetti and coworkers worked diligently, and, recogniz-
ing that ACE was a metallo-enzyme, they visualized the binding of a smaller
snake-venom peptide SQ20475 (
111
) with ACE; they modeled an acyl-proline
with a sulfhydryl substitution at the zinc binding site, which led to the design
and synthesis of captopril (
112
) as an orally active highly effective antihyper-
tensive clinical agent. Additional application of the rational design by Patchett
and coworkers led to the synthesis of enalapril (
113
) and other clinically relevant
oral ACE inhibitors (138).
β
-hydroxy-
δ
