LY2452473 is a selective androgen receptor modulator (SARM), with potential tissue-selective androgenic/anti-androgenic activity. Upon oral administration, LY2452473 acts as an agonist in select tissues and organs, including skeletal muscle, bone and the penis, thereby binding to and activating androgen receptor (AR) while acting as an antagonist in the prostate, thereby blocking AR activation and AR-mediated cellular proliferation. This may improve muscle mass and strength, bone formation, and erectile dysfunction while not stimulating growth of the prostate. Eli Lilly was developing LY 2452473/tadalafil combination for the treatment of erectile dysfunction. In addition, Eli Lilly is studying the use of a targeted LY 2452473 therapy, as a possible improvement in quality of life for prostate cancer patients who have undergone radical prostatectomy.

F-351 (Hydronidone), a pyridine derivative, is a non-steroidal antiinflammatory drug. It inhibits hepatic stellate cell proliferation and also the TGF-β signaling pathway. Shanghai Genomics is developing F-351 for the treatment of liver fibrosis induced by HBV chronic hepatitis (HBV). For additional indications, F-351 has the potential to be further developed for Non-alcoholic steatohepatitis (NASH) liver disease, Non-alcoholic fatty liver disease (NAFLD) and chronic kidney failure.

MedImmune is developing MEDI 9197 (formerly 3M-052), a toll-like receptor 7/8 dual agonist, for the treatment of cancer. MEDI9197 has been designed to activate a broad range of innate immune cells through targeting of both TLR 7 and 8, leading to a more robust adaptive immune response. A TLR7 and 8 dual agonist can additionally convert immune suppressive cells in the tumor to those with anti-tumor properties, allowing the generation of an effective anti-tumor response. MEDI9197 is uniquely designed for intratumoral injection, allowing the compound to be retained in the tumor and provide specific immune activation, enhancing its safety and tolerability profile.

PG-116800 is a member of the hydroxyproline-based hydroxamic acid class of matrix metalloproteinase (MMP) inhibitors. PG-116800 did not modify matrix structure in osteoarthritic patients. Also, it had unexpected side effects on muscle and skeleton; it limited joint mobility, and caused arthralgia, hand oedema, palmar fibrosis, Dupuytren’s contracture and persistent tendon thickness or nodules. PG-116800 failed to reduce left ventricular remodeling or improve clinical outcomes after myocardial infarction.

Pfizer was developing PF-04991532, a potent and selective hepatoselective glucokinase activator. PF-04991532 ameliorates hyperglycemia without causing hepatic steatosis in diabetic rats. F-04991532 reduced plasma glucose concentrations independent of changes in insulin concentrations in a dose-dependent manner both acutely and after 28 days of sub-chronic treatment. PF-04991532 may offer glycemic control without inducing hepatic steatosis supporting the evaluation of tissue specific activators in clinical trials. In 2012, Pfizer discontinued the development of the compound.

Napsagatran [RO 466240], a reversible and highly selective thrombin inhibitor, was in development with Roche for use in myocardial infarction and thrombosis. Napsagatran efficiently inhibits and delays thrombin generation in human coagulating plasma. This reduced thrombin generation might be caused by inhibition of thrombin-mediated feedback reactions during blood coagulation. Ro 46-6240 inhibited clot-bound thrombin three times more potently than fluid-phase thrombin (IC50 19 vs 56 ng/ml) while hirudin was two times (IC50 8 vs 3 ng/ml) and heparin six times (IC50 1,205 vs 200 ng/ml) less active against clot-bound thrombin compared with fluid-phase thrombin.

PF-3758309 was developed as an ATP-competitive inhibitor of PAK4. In cells, PF-3758309 inhibits phosphorylation of the PAK4 substrate GEF-H1 (IC50 = 1.3 nM) and anchorage-independent growth of a panel of tumor cell lines (IC50 = 4.7 nM). PF-3758309 blocks the growth of multiple human tumor xenografts, with a plasma EC50 value of 0.4 nM in the most sensitive model. PF-3758309 is antiproliferative and induces apoptosis in an HCT116 tumor model.