LX4211 - Lexicon Pharmaceuticals

David B. Rawlins, senior director of medicinal chemistry at Lexicon Pharmaceuticals in Princeton, N.J., discussed LX4211, an orally administered drug candidate for type 2 diabetes. The molecule is a dual inhibitor of sodium-glucose transporters 1 and 2, also known as SGLT1 and SGLT2.

Inhibiting the SGLT2 transporter boosts the release of blood glucose from the body through the urine. The transporter is the target of several experimental diabetes treatments, including Bristol-Myers Squibb and AstraZeneca’s dapagliflozin, which this January received a thumbs-down from the Food & Drug Administration (CENtral Science, The Haystack, Feb. 2). SGLT1 hadn’t previously been touted as a diabetes drug target. Despite its role in glucose absorption in the gastrointestinal tract, people lacking a functional gene for SGLT1 often can’t tolerate glucose and galactose in their diet and develop severe diarrhea in response to it, a condition called glucose-galactose malabsorption.

Lexicon researchers forged ahead with their dual-inhibitor approach after studying knockout mice from their library, which contains knockouts of just under 5,000 different enzymes, secreted proteins, and receptors. When they gave the library mice a high dose of glucose, the SGLT1 and SGLT2 knockout mice both had among the lowest levels of glucose and insulin in their blood afterward.

Most inhibitors of sodium-glucose transporters contain d-glucose—a moiety inherited from the natural product phlorizin. First isolated from apple tree bark in the 1830s, phlorizin was once evaluated as a potential diabetes treatment. Lexicon’s chemists realized that d-glucose’s C-6 methyl and hydroxyl were not critical for binding to the transporters, so they decided to try inhibitors based on the scaffold of l-xylose, a nonnatural sugar. This sugar has the same relative configuration of the secondary alcohols as is found in d-glucose, but the team surmised it would be less likely to bind to other glucose receptors, Rawlins said in San Diego (J. Med. Chem., DOI: 10.1021/jm900951n).

When Lexicon chemists incorporated a sulfur atom into their l-xylose scaffold to form thioglycosides, the team saw a big boost in their drug candidates’ activity in animals. They chose LX4211, a methyl thioglycoside, as their dual inhibitor because larger thioglycosides lost the ability to inhibit SGLT1.

In a Phase IIa clinical trial to test LX4211’s efficacy in a small number of type 2 diabetics, patients on the experimental drug had decreased blood glucose levels compared with patients on placebo, as well as lower triglycerides, blood pressure, and body weight. On the basis of data from mice, the team thinks blocking SGLT1 in the intestine also impacts gut hormones that regulate food intake. Rawlins added that the company hasn’t seen signs of glucose-galactose metabolism issues in animals or patients at clinically relevant doses. “Our biggest lesson was that you should follow your in vivo results, even if it goes against the dogma of the day,” Rawlins told C&EN. Lexicon is currently completing Phase IIb clinical trials of LX4211.