Statins: protection against heart attacks and strokes—hallelujah!

The class of drugs known as statins is very effective in lowering plasma cholesterol levels; these drugs have been established to reduce the frequency of heart attacks and strokes in multiple settings. The statins are inhibitors of an enzyme known as HMGR, an enzyme on the metabolic pathway to cholesterol. The first statin, mevastatin, was discovered by Japanese scientists in a fermentation broth from an organism cultured from a soil sample taken near a golf course. Mevastatin established the efficacy of HMGR inhibitors as cholesterol-lowering agents but ultimately failed as a drug candidate. The first marketed statin was lovastatin (Mevacor), isolated at Merck from a fermentation broth. Pravachol followed from Squibb, as did simvastatin (Zocor) from Merck and subsequently several other, notably Lipitor and Crestor. They are among the most widely prescribed drugs in the world.

Basic research, snake venoms, and ACE inhibitors: Ondetti, Cushman, and Patchett

Angiotensin-converting enzyme (ACE) inhibitors are highly important drugs for control of blood pressure, chronic heart failure, and kidney protection. The discovery of ACE inhibitors derived from several basic research sources. The peptide angiotensin-II was demonstrated to contract the smooth muscle layer lining the vasculature and to cause retention of water in the body. Both conditions tend to raise blood pressure. It follows that an inhibitor of the enzyme that promotes the synthesis of angiotensin-II, ACE, would relax the vasculature, decrease water retention, and lower blood pressure. The questions were to confirm this hypothesis and discover ACE inhibitors. The chemistry of snake venoms helped with both. A peptide isolated from a venomous snake proved to be an ACE inhibitor and, while not suitable to be a drug, lowered blood pressure in clinical trials, confirming the hypothesis. In addition, the structure of the venom peptide provided an important clue to the structure of ACE inhibitors. The final key was provided by the discovery of a novel inhibitor design concept in an academic laboratory. Pulling this information together led to the discovery of the following ACE inhibitors suitable for clinical use: Capoten, Vasotec, Zestril, and others.

Seduced by drug discovery

The opportunity to see the fruit of scientific work in one’s own lifetime proved a compelling motivation to leave a productive academic career in biochemistry and join the pharmaceutical industry, the Merck Research Laboratories specifically. Beginning with work on benign prostatic hypertrophy, the work became involved with statins, angiotensin-converting enzyme inhibitors, and other areas of drug discovery. Taken from experiences at Merck and elsewhere, eleven adventure stories in drug discovery are presented, ten successes and one notable failure. It is emphasized that most of what scientists start in drug discovery eventually fails, but that pharmaceutical scientists are nonetheless enthusiastic about prospects for success in their work and dedicated to it. The organization of this book is provided.

The perils of Primaxin

Primaxin is one of the most effective antibiotics introduced into medical practice in the past few decades. It is a single-pill combination of two agents, an unusual β‎-lactam antibiotic and an inhibitor of an obscure kidney enzyme that abolished the efficacy of the β‎-lactam in that organ. The initial discovery was a β‎-lactam antibiotic (think penicillin, amoxicillin) named thienamycin from a fermentation broth. Thienamycin had marvelous antibiotic properties, potent against many microorganisms resistant to earlier β‎ lactams, but was notoriously unstable. Once the unusual structure of thienamycin was unraveled, structural modifications were started. A critical chemical modification resulted in a new agent, imipenem, that retained the antibiotic properties of thienamycin but was stable. A second drug discovery effort resulted in an inhibitor of the kidney enzyme, cilistatin. A combination of the two created Primaxin.

Fludalanine: nice try but no hallelujah

Fludalanine was one of the most promising antibiotics of its generation: a simple inexpensive molecule having a novel mechanism of action highly effective against problem bacteria. It ultimately failed as a consequence of potential toxicity to patients resulting from one of its metabolites. The starting point for fludalanine is the simple molecule D-fluoroalanine, a potent inhibitor of alanine racemase, the enzyme that supplies the amino acid D-alanine for bacterial wall synthesis. D-Alanine has no role in human metabolism. Fludalanine is derived from D-fluoroalanine by an isotopic substitution designed to slow its rate of metabolism. Remarkably, at high concentrations of fludalanine, bacteria actually use the antibiotic for cell wall synthesis. To prevent that, another inhibitor of a distinct enzyme required for bacterial cell wall synthesis, pentizidone, was combined with fludalanine: problem solved. However, long-term safety studies in rodents revealed that fludalanine caused vacuole formation in the brain, called spongy brain. The toxicity was traced back to a metabolite of fludalanine, and the toxicity of that molecule in rodents was established. Unhappily, levels of that metabolite proved too high in patients to ensure their safety. That was the end of a highly promising effort to add an important antibiotic to clinical practice.

Diabetes breakthroughs: Thornberry and Weber

Januvia and Janumet are important additions to the array of drugs that are employed to treat type 2 diabetes. Januvia (sitagliptin) works by an entirely novel mechanism: it is a potent and specific inhibitor of an enzyme known as DPP-4 (dipeptidyl peptidase-4). DPP-4 promotes the destruction of a peptide known as GLP-1 (glucagon-like-peptide-1), an incretin. Incretins are agents that stimulate the secretion of insulin and repress the secretion of glucagon. Both actions tend to normalize glucose levels. Indeed, clinical trials with GLP-1 have shown that this peptide normalizes blood glucose levels in both the fed and fasted states. GLP-1 must be given by injection and is not suitable for routine use by diabetic patients. However, an inhibitor of the enzyme that degrades GLP-1 is the functional equivalent of administration of GLP-1. Januvia acts in exactly this way. Janumet is a combination product in which Januvia is combined with metformin, an effective anti-diabetes agent that has been employed for many years. There are now a number of gliptins (DPP-4 inhibitors) in clinical use for type 2 diabetes.

Proscar and Propecia: the Gary and Jerry show

Tracking down the metabolic basis of a remarkable human single-gene genetic disease provided the insight required to discover drugs to prevent prostate gland growth in aging men (benign prostatic hyperplasia, BPH) and prevent hair loss in men (male pattern baldness). Victims of this genetic disease are born with the appearance of females and are recognized as such. However, at puberty, they undergo a transformation and develop the characteristics of males. The underlying genetic defect is a mutation in the gene that codes for the enzyme 5-alpha reductase (5AR), which promotes conversion of testosterone (T) into the more potent male sex hormone dihydrotestosterone (DHT). Lack of sufficient DHT in utero prevents the full expression of male anatomy at birth, an issue that is corrected at the time of puberty when a surge of male sex hormones occurs. These men have a very small prostate gland that never grows, do not lose their hair, and do not get acne. This strongly suggests that DHT is the causative agent of BPH, male pattern baldness, and acne. An inhibitor of 5AR would create the functional equivalent of the genetic defect and would be expected to be effective in shrinking an enlarged prostate gland and slowing or preventing hair loss and acne in men. Finasteride is such an inhibitor and has met expectations. It is marketed as Proscar for BPH and Propecia for male pattern baldness. Finasteride is a teratogen (can cause birth defects) and has not been developed for acne for that reason.

HIV protease inhibitors: weapons in the war against HIV/AIDS

The discovery of drugs for AIDS has converted these infections from a death sentence into a chronic infectious disease. The research of Luc Montagnier and Robert Gallo established that HIV is the cause of AIDS, subsequently known as HIV/AIDS, the most deadly infective disease known. Basic research into the life cycle of HIV revealed a number of potential molecular targets for treatment of the infection. Among these are HIV protease and reverse transcriptase, enzymes required for the propagation of the virus in human T cells. AZT (azidothymidine), a reverse transcriptase inhibitor, was the first drug approved for treatment of HIV/AIDS. It was followed by three HIV protease inhibitors: saquinavir, ritonavir, and indinavir (Incivek). The last of these was discovered through a structure-based drug design strategy and proved to be a turning point in therapy for HIV/AIDS. This drug discovery effort was conducted in an atmosphere of prejudice, ignorance, snake oil medicine, and intense activism by Act Up and others. The net result is a miracle of modern medicine.

The discovery of taxol: Wall, Horwitz, Holton

Taxol is a widely employed drug for chemotherapy of breast cancer and finds use for ovarian and lung cancer as well as for Kaposi’s syndrome. Getting from the discovery of taxol to approval for treatment of cancer took 30 years. The molecule was discovered in the Pacific yew tree, where it occurs in very small amounts. Early studies proved encouraging but not striking enough to generate real enthusiasm for pushing taxol forward. Then Susan Horwitz discovered its mechanism of action—it prevents the dissolution of microtubules—and enthusiasm strengthened. The problem at that stage was getting enough taxol to treat patients. Environmentalists were concerned that harvesting trees for taxol would destroy basically all of the Pacific yew trees in old forests, a legitimate concern. The discovery of a taxol precursor in the English yew, where it occurs in substantial amounts, coupled with the synthesis of taxol from that precursor solved the supply issue. It is now made by total synthesis. Determination by a few scientists over decades brought this important cancer drug into practice.

Avermectins: molecules of life battle parasites

Avermectins are effective anti-parasitic agents in human health, animal health, and agriculture. A family of closely related avermectins was discovered in Japan in a fermentation broth of a previously unknown microorganism. These molecules were discovered once in screening 250,000 broths. They were developed initially for animal health by Merck, and a number of agents reached the market: for food animals, horses, pets. The derivatives of the avermectins that are marketed are known as ivermectins. Their use for parasitic diseases of humans was explored, and they were found to be highly effective for river blindness and filariasis (elephantiasis), diseases that afflict the poor in many areas but especially in sub-Saharan Africa The drugs are made available at no cost to victims of these diseases. There is hope that these parasitic diseases can be eradicated. The avermectins also find use in agriculture.