Following up on the discussion of fragment-derived compounds that have made it into the clinic, the first 2009 issue of PNAS describes the discovery of indeglitazar, which I believe is the USAN name of Plexxikon’s PLX-204/PPM-204. Indeglitazar is a pan-agonist of the peroxisome proliferator-activated receptors (PPARs), and has been in clinical trials for treatment of type 2 diabetes.
Plexxikon’s version of fragment-based screening, “scaffold-based discovery,” entails screening several thousand small to medium sized fragments (150-350 Da) in a biochemical assay, followed by crystallographic analysis of active molecules. In the current case, the researchers screened their collection against PPAR alpha, gamma, and delta, looking for molecules that activated two or more. After the primary screen, 170 molecules were characterized crystallographically, and about a quarter produced at least one structure. The substituted indole fragment (below) showed very weak activity, but bound snugly in a large pocket with its NH positioned toward a second pocket. Structure-guided design led to the more potent phenyl sulfonamide shown in the middle of the figure, and synthesis of just 20 additional compounds resulted in indeglitazar, which activates PPARs alpha, gamma, and delta. Ligand efficiency remained fairly constant throughout optimization.
Indeglitazar is a full agonist of PPAR alpha but only a partial agonist of PPAR gamma and delta; this may provide a better side effect profile than full activators. The molecule shows impressive pharmaceutical properties (high oral bioavailability, long half-life, etc.) as well as promising activity in mouse and rat models of diabetes (lower blood glucose, insulin, total cholesterol, triglycerides, free fatty acids, etc.). In contrast to other PPAR agonists, which sometimes cause weight gain, indeglitazar also caused weight loss in rodent and primate models; the authors suggest this could be because it affects all three PPARs.
Although indeglitazar was advanced to phase 2 trials in collaboration with Wyeth, increasing concerns over the potential side effects of PPAR agonists have caused Wyeth to discontinue development of this compound for diabetes, and as of November of 2008 the molecule was available for licensing.
Nonetheless, this is an impressive story, and appears to be the first example of using fragment-based methods to discover an agonist, as opposed to an inhibitor.