Issue Date: April 19, 2010
The Gastric Bypass Pill
Bariatric surgery is meant to help people lose weight, but it often has a far more profound effect: Doctors see many of their patients go into remission from type 2 diabetes after the intense operation.
In the aftermath of the Roux-en-Y procedure, a radical rerouting of the gut, the recovery from diabetes happens so fast that many patients can stop taking their medications by the time they leave the hospital. Researchers suspect that something far more complicated than fat loss is causing their recovery.
For medicinal chemists, this phenomenon provides a tantalizing avenue for developing diabetes drugs that target the gastrointestinal tract. If they can figure it out, they may be able to mimic the metabolism-fixing effects of bariatric surgery with a pill. At a symposium sponsored by the Division of Medicinal Chemistry at last month’s American Chemical Society national meeting in San Francisco, researchers met to discuss advances in this area.
Bariatric surgery seems to have a profound effect on chemical signaling in the intestine. By rerouting the digestive tract, bariatric procedures cause gastrointestinal contents to bypass one part of the gut and add extra stimuli in another area.
Perhaps a drug that can mimic a few of those effects could restore human metabolism to a healthy, nondiabetic state. But the biochemistry of metabolism is extremely complicated, making identification of the most important players in the signaling game tricky business. The intestine sends over 100 different messages via peptides alone. And then there are proteins, carbohydrates, bile acids, lipids, and other substances to consider.
One particularly important class of signaling molecules is bile acids. The steroid derivatives were viewed as little more than detergents until 1999, when it became clear that they act as hormones and trigger the nuclear farnesoid X receptor (FXR), a protein that was misunderstood for many years. Despite its name, FXR does not respond to farnesol, but it does take cues from a variety of bile acid ligands and regulates the expression of genes involved with bile acid metabolism, as well as cholesterol, lipid, and glucose metabolism (J. Med. Chem. 2005, 48, 5383).
Bile acids also modulate metabolism by activating TGR5, a G-protein-coupled receptor that was discovered in 2002 by several Japanese groups. It is expressed in liver, muscle, brown adipose, and intestinal tissue.
After bypass surgery, bile acids may make it to the lower intestine faster. Once there, they modulate energy homeostasis in several ways. “Through their interaction with the FXR and TGR5 receptors, bile acids are able to influence many pathways involved in glucose and lipid metabolism,” Roberto Pellicciari, a medicinal chemistry professor at the University of Perugia, in Italy, said at the symposium.
Pellicciari formed a long-standing partnership with Intercept Pharmaceuticals that has led to the development of two different bile acid derivatives as treatments for metabolic disease.
The team began their search for a suitable FXR trigger, or agonist, by screening a large number of bile acid derivatives. During that effort, they had the good fortune to test a subtle variation of one of FXR’s endogenous ligands, chenodeoxycholic acid. By adding a single ethyl group to that steroidal molecule, they obtained a remarkably potent candidate, INT-747, which is now entering Phase III trials. The first indication for INT-747 may be for primary biliary cirrhosis, a disease that often accompanies diabetes. The same drug is also in clinical trials for a diabetes indication.
While screening bile acid derivatives to find a suitable TGR5 agonist, Pellicciari and his colleagues discovered the importance of two alkyl moieties on the steroid scaffold. They also noted that the bile acid cholic acid can reverse diabetes in obese mice at extremely high doses. By incorporating the pair of slight alkyl modifications into cholic acid’s side chain and b ring, they developed a potent drug candidate, INT-777, which is entering clinical trials as a treatment for diabetes. It was developed in collaboration with Johan Auwerx and his team at the Swiss Federal Institute of Technology, Lausanne (J. Med. Chem. 2009, 52, 7958).
Pellicciari explained that INT-777’s interaction with TGR5 triggers the release of glucagon-like peptide-1 (GLP-1), a hormone that helps the pancreas function properly. The drug also increases insulin sensitivity, a natural response to glucose that is dysfunctional in most diabetics, and it promotes the conversion of thyroid hormone T4 into T3, which stimulates energy production. Takeda and GlaxoSmithKline are also pursuing drugs that affect TGR5.
Another set of chemical signals that may be altered by bariatric surgery are the natural amides of fatty acids, which are agonists of a G-protein-coupled receptor known as GPR119. Arena Pharmaceuticals has been investigating the biology of that receptor as a diabetes drug target for more than a decade. It is found in some insulin-producing pancreatic β cells and in L and K cells, which release key signaling hormones in the gut after meals.
“Remarkably, this exquisite pattern of expression allows GPR119 agonists to elicit endocrine hormonal changes very similar to that achieved with bariatric surgery,” said Rob Jones, senior director of medicinal chemistry at Arena. For example, compounds that activate GPR119 trigger a proper response to glucose by augmenting the release of several key signaling peptides including insulin, GLP-1, and the appetite-decreasing peptide PYY.
GLP-1 promotes glucose-sensitive insulin secretion from pancreatic β cells. Several diabetes drugs that delay the degradation of GLP-1 by inhibiting an enzyme called DPP-IV are already on the market. Jones mentioned that Arena’s GPR119 agonists could complement such drugs.
During the ACS meeting, Jones described the structure-activity relationship work that led to Arena’s first-generation GPR119 agonist, JNJ-28630355, which is a trisubstituted pyrimidine. Working in collaboration with Ortho-McNeil-Janssen, Arena has ushered a second-generation compound, dubbed APD597, into Phase I clinical trials.
Bariatric surgery may also affect triglyceride signals. Those molecules cannot be transported from the intestine into systemic circulation directly. They must be broken down to enter the bloodstream and then reassembled. Researchers have found evidence that interfering with triglyceride reassembly could benefit diabetes patients.
For example, mice with knocked-out diacylglycerol acyltransferase 1 (DGAT-1), an enzyme that reassembles triglycerides, are resistant to developing diabetes, said Robert Dow, an associate research fellow at Pfizer. The same goes for mice that have had that enzyme knocked down by antisense RNA molecules.
On the basis of such evidence, Pfizer took an interest in targeting DGAT-1. They licensed a preclinical compound from Bayer, but it had too many safety problems, and eventually it got dropped from further development. At the same time, Pfizer researchers set themselves about the task of discovering a better molecule, one with chemical and safety profiles completely different from those of Bayer’s compound.
The lead compounds for Pfizer’s internal DGAT-1 discovery program also raised several red flags, including the potential for phototoxicity and formation of reactive metabolites. After an exhaustive effort, Pfizer researchers created a DGAT-1 inhibitor series with a good safety profile. This led to the discovery of PF-04620110, a compound that potently inhibits DGAT-1 and produces increased levels of the key gut hormones GLP-1 and PYY in preclinical efficacy models. PF-04620110 is currently in Phase I clinical trials to treat diabetes.
Medicinal chemists have plenty to learn about bariatric surgery and its effect on diabetes. Michael Bishop of GlaxoSmithKline urged his audience to look closer at the role of enteroendocrine cells, which produce and excrete bioactive peptides from the intestinal tract. Others touted examining the role of gastrointestinal tract contents, investigating genetic factors, and hunting for new signaling pathways and molecules.
“Discovering the key drivers to diabetes control post-Roux-en-Y could lead to new pharmaceutical approaches to metabolic disease,” Bishop said.
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