Adona Andoy Canta

01 02 03

Member of the group

IntroductioN
Discovery
Development
 HMG-COA
REDUCTASE
INHIBITORS
• Also known as the “statins” which are a class of drugs used to lower
cholesterol levels by nhibiting the enzyme HMG- COA reductase,
which plays a central role in the production of cholesterol in the liver,
which prodices about 70% of cholesterol in the body.
• Statins are one of the most successful classes of prescription drugs,
but regulators in the United States have not yet approved them for
OTC use.
• Although low dose statins can be given over the counter, they are not
generally made available by pharmaceutical firms, and making the
most effective and powerful versions safely available, without a
 Classification of
Sourc statins Solubilit
e y

Natural: Lipophilic
• Pravastatin • Simvastatin
• Simvastatin • Atorvastatin
• Lovastatin • Fluvastatin

Synthetic Hydrophilic
• Atorvastati • Pravastatin
n • Rosuvastatin
• Fluvastatin
• Akira Endo was born in November, 1933 to a farming family
in Hagishiyuri, Honshu Island, Japan. Following completion of
his degree training at the School of Agriculture at Tokohu
University, he went to work for the Sankyo pharmaceutical
company in Tokyo.

• During his search for antibiotic compounds produced by fungi

in 1971, Endo discovered a class of compounds that appeared
to lower plasma cholesterol levels.
• Two years later, the research group isolated a compound
structurally similar to hydroxymethylglutarate (HMG) that
inhibited the incorporation of acetate. The compound was
proposed to bind to the reductase enzyme and was named
compactin.

• Mevastatin or compactin is a cholesterol-lowering agent

isolated from Penicillium citinium. And was the first
discovered agent belonging to the class of cholesterol-
lowering medications.
Discovery
of Suspension Roy Vagelos’
Lovastatin of Crucial
Developme Decision
Discontin nt of
ue of Lovastatin Early FDA
Compacti Involveme
n nt
 Discovery of lovastatin

• At the end of the 1970s other pharmaceutical companies to

begin searching for another statin.
• In July 1976, Merck Research Laboratories, signed a
confidentiality agreement with Sankyo and obtained samples of
compactin and confidential experimental data.
• Under the direction of Alfred Albert, Merck set out to find its
own statins .
• In February 1979 Alfred W. Albert isolated a statin very similar
to compactin, called mevinolin (lovastatin) from the fungus
Aspergillus terreus
 Discontinue of
compactin

• In August 1980 Sankyo discontinued the clinical development

of compactin.

• The drug apparently caused lymphoma in dogs when given in

high doses.
 Suspension of
Development of
lovastatin
• In April 1980, Merck began preliminary clinical studies of
lovastatin
• But after 5 months, in September 1980, they discontinued the
clinical trials because of rumors that compactin caused cancers in
dogs.
• For this reason Merck halted studies on lovastatin.
 Early fDA involvement
• Following Merck's decision to terminate clinical trials, FDA became actively
involved in maintaining interest in the development of the statins.
• Dr. Sol Sobel at FDA took key decisions to keep statins alive.
• In July 1982, Merck made lovastatin available, under an arrangement
approved by the FDA to Roger Illingworth of Oregon Health Sciences
University and Scott Grundy and David Billheimer of the University of Texas
Southwestern Medical Center.
• Although Merck did not have an IND at the time, IND's were granted to
Illingworth and Grundy under a process that included Merck's agreement to
allow FDA to provide the researchers access to the Drug Master File.
 ROY VAGELOS’
CRUCIAL DECISION
• In March 1984, Merck submitted an IND for lovastatin.
• Thereafter, the new drug application for lovastatin was approved only
nine months after its submission to FDA
• This was one of the shortest approval times for a new drug application
up to that time.
• The decision to approve cholesterol lowering agents for marketing at this
time was based on the surrogate of lowering LDL cholesterol (not on
cardiovascular endpoints).
• This surrogate was a key component in shortening the review time for
lovastatin, and the drug was released for marketing in 1987.
• On September 1, 1987, lovastatin became the first statin to
be approved in the United States by the Food and Drug
Administration (FDA). This agent is responsible for
revolutionizing the treatment of hypercholesterolemia,
initially achieving peak annual sales of more than $1 billion
USD.
Currently, there are seven statins available for
clinical use:
• lovastatin (1987),
• simvastatin (1988),
• pravastatin (1991),
• fluvastatin (1994),
• atorvastatin (1997),
• rosuvastatin (2003), and
• pitavastatin (2009).
Another drug, cerivastatin, was approved by
the USFDA and launched in January 1998, but
was subsequently withdrawn from the market
in August 2001 because of adverse event
reports of rhabdomyolysis.
 Statin- Induced diabetes
• Although safe and generally well tolerated, emerging data have
suggested that statins are associated with an increased risk of new-
onset diabetes (NOD).
• Several meta- analyses of clinical trials conducted during the years
of 2008, 14 showed the association of NOD in the range of 527% in
patients and about 48% in menopausal woman treated with different
statins.
• All the statins including hydro-philic (e.g., pravastatin and
rosuvastatin) as well as hydrophobic (e.g., atorvastatin, lovastatin,
pitavastatin, and simvastatin) have been reported for their
association for NOD risk in dose-dependent manner.
• For these reasons, USFDA added a warning about diabetes risk to
REFERENCES:
https://www.cell.com/fulltext/S0092-8674(08)01127-6
https://www.slideshare.net/sanjoydr/statin-46208142PENYEBAB
https://journals.sagepub.com DAMPAK
Innovative Approaches in Drug Discovery PENANGGULANGA
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