Triumph of the Heart: The Story of Statins

Triumph of the Heart: The Story of Statins

Jie Jack Li

Language: English

Pages: 224

ISBN: 0195323572

Format: PDF / Kindle (mobi) / ePub

Over 25 million people in the U.S. alone have benefited from statins--such drugs as Lipitor, Zocor, Crestor, Pravachol, and other cholesterol-lowering medicines--in preventing stroke, heart attack, and other forms of coronary heart disease. But how did these remarkable, life-saving drugs come into being? In Triumph of the Heart, Dr. Jie Jack Li, a medicinal chemist and expert on drug discovery, tells for the first time the fascinating story of statins. Drawn from discussions with many scientists involved in the discovery and development of these drugs, the book illuminates the human side of science by revealing the role played by persistence, luck, and sudden insight that characterize major discoveries. For scientists in the drug industry, health care professionals, students of medicine, and all those intrigued by the basic human drive to explore and discover, Triumph of the Heart offers a compelling view of one of the most important drug discoveries of our time.

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success of Lopid (gemfibrozil) was a prime example. In the early 1950s, Imperial Chemical Industries Ltd. (ICI) in England discovered that clofibrate possessed high activity for lowering serum cholesterol. ICI had sold clofibrate under the trade name Atromid-S since 1958. Four years later, J. M. Thorp and W. S. Waring of ICI published a paper in Nature summarizing clofibrate’s effects on lipids.12 The Nature paper incited a flurry of research in the drug industry, resulting in many second- and

the team took a “shotgun” approach, exploring a variety of heterocycles in place of Roth’s pyrrole. Eventually, each chemist on the team took on a different heterocycle as the core structure. Roth chose to continue with his pyrrole; Sliskovic chose pyrazole; Chucholowski, pyrimidine; Picard, quinoline; and Creswell, pyridine. After months of work in assembling the core pyrazole structure and attaching the best side chain similar to that of mevastatin, in mid-1985, Sliskovic finally arrived at

historically had done few licensing deals), ParkeDavis decided to abandon the pyrazole series. This event was a crushing defeat for the team, and they had to regroup and examine their remaining options. In drug discovery, one needs to have persistence—few, if any, compounds a chemist makes will become marketed drugs. discovery of lipitor 93 CI-971 After the team decided to drop PD-123588, the only remaining option seemed to be Roth’s PD-123832. PD-123832 was a more complicated molecule than

the level of cholesterol. They include fibrates, cholesterol ester transfer protein (CETP) inhibitors, peroxisome proliferator–activated receptor (PPAR) agonists, nicotinamide receptor agonists as exemplified by nicotinic acid, and acylCoA: cholesterol acyltransferase (ACAT) inhibitors. One biotech company, Isis Pharmaceuticals, recently reported a successful midstage trial for a cholesterol-lowering drug, but the technology to make that drug, known as antisense technology, has had a troubled

Therapeutics compound. Running a small biotechnology firm is not without its perils. In March 2002, Esperion stock was at an all-time low. Newton had to lay off a quarter of his workforce, one of the hardest things he had to do. But things began to look up when positive phase II results were published. Newton then persuaded Dr. Steven Nissen of the Cleveland Clinic to conduct studies on ETC-216 using intravascular ultrasound—a bioimaging method that uses a tiny ultrasound probe inserted into the

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