Of course, there is still a strong need for HIV/AIDS treatments as well as preventive approaches. Bart De Corte, principal scientist, drug discovery at Johnson & Johnson Pharmaceutical R&D (Spring House, PA), described 15 years of medicinal chemistry research into non-nucleoside reverse transcriptase inhibitors (NNRTIs). This has led the company to TMC125 (Etravine), currently in Phase II in HIV/AIDS patients.
The first anti-HIV NNRTIs were in the TIBO chemical structure class, followed by a number of other small molecule structural types, all of which could bind to the RT enzyme in HIV.
"We began with wild type HIV, but then single and double mutants came along and these had to be tackled," explained Dr. De Corte. The DATAs chemical family were potent inhibitors of wild type HIV-1 and single mutants, and the DAPYs family worked on both single and double mutants.
These research efforts culminated in the compound TMC 125, which compares very favorably with other currently marketed NNRTIs in its activity against HIV-1 and mutant strains. Trials in both treatment-nave and NNRTI treatment-resistant patients have shown a dramatic decrease in viral load.
Meanwhile, J&J has also been looking at TMC278 (Rilpivirine) which is proving to be efficacious as monotherapy given over seven days. "If anything, TMC278 is better than TMC 125," said Dr. De Corte. "We are really thrilled about this compound."
Hartmut Rehwinkel, Ph.D., principal scientist at Schering (Berlin), described the development of selective glucocorticoid receptor agonists (SEGRAs). There is a clear need for alternatives to conventional glucocorticoids, also known as steroids, which act by two different mechanismstransactivation and transrepression. The latter is thought to favor anti-inflammatory effects over side effects.
"We have identified compounds that show sufficient dissociation between anti-inflammatory and side effect activity," said Dr. Rehwinkel. For instance, compound A does not increase blood glucose levels in subcutaneous application in mice compared to prednisolone. It also induces less skin atrophy than standard glucocorticoids and has fewer systemic side effects.
Jrg Holenz, director, medicinal chemistry, Esteve Laboratories (Barcelona, Spain), spoke about new and selective ligands that bind to 5-HT6, a recently cloned member of the serotonin receptor family which is a GPCR expressed exclusively in the brain which may have a role in several CNS conditions.
Esteve, a recent entrant into this field, has been looking at a pharmacophore framework model to discover leads. This involves aligning molecules from the literature to discover a common core which can be built upon. "This gave us an idea of a molecule which had all the necessary features," said Dr Holenz.
The model was then applied to the discovery of various series of novel potential ligands. Application of structure affinity relationships then led to a number of compounds with a high degree of selectivity for the 5-HT6 receptor. One of these has already shown good results in cognitive enhancement and combatting obesity in animal models.
A new approach to treatment of type 2 diabetes was described by Max Dang, Ph.D., associate director of medicinal chemistry, Metabasis Therapeutics (San Diego), involving the development of novel phosphonates that can inhibit the enzyme Fructose 1,6-bisphosphatase (FBPase).
"More than 50 percent of diabetics do not meet the American Diabetic Association's therapeutic targets, even given existing drugs," commented Dr. Dang.
Hepatic glucose production (HGP) involves two pathwaysglycogenolysis and gluconeogenesis. FBPase is involved in the latter and is known to be upregulated in diabetes. The enzyme therefore represents a potential new drug target, and one that should be safe, given that people with a genetic deficiency of FBPase are normal.
The normal substrate of the enzyme is AMP so the company wanted to design novel AMP mimetics, starting off with novel benzimidazole phosphonates, then moving to thiazole phosphonates, which proved orally bioavailable as prodrugs.
The company is now working with novel bisamidate prodrugs of organophosphonates, which have a good to high oral bioavailability and are proving efficacious in animal studies.