Jennifer A. Williams

Inhibitors of cathepsin s

Cathepsin B is an abundant and ubiquitously expressed cysteine peptidase of the papain family. It is involved in many physiological processes, such as remodeling of the extracellular matrix (wound healing), apoptosis, and activation of thyroxine and renin. In addition to its physiological roles, cathepsin B is important in many pathological processes, such as inflammation, parasite infection and cancer, where it is highly up-regulated. In cancer patients, elevated cathepsin B activity correlates to poor therapy outcome. Therefore, it is not surprising that the use of cathepsin B inhibitors reduces both tumor cell motility and invasiveness in vitro. This review summarizes recent developments in cathepsin B inhibition. To date, numerous protein inhibitors of cathepsin B have been described, some of which are of endogenous origin and function as regulators of cathepsin B activity in the cell, such as the cystatins. In addition, some exogenous protein inhibitors of cathepsin B have been isolated from various natural sources, and the use of X-ray crystal structures of cathepsin B complexed with such protein inhibitors has resulted in the design and synthesis of many new small-molecular-weight compounds as inhibitors of cathepsin B. These synthetic compounds generally contain an electrophilic functionality that reacts with cathepsin B. In the present review, these inhibitors are divided according to their mechanisms of action, as reversible and irreversible, and then further subdivided into groups for their full descriptions.

Discovery of inhibitors of the channel-activating protease prostasin (CAP1/PRSS8) utilizing structure-based design.

Structure-based design was utilized to guide the early stage optimization of a substrate-like inhibitor to afford potent peptidomimetic inhibitors of the channel-activating protease prostasin. The first X-ray crystal structures of prostasin with small molecule inhibitors bound to the active site are also reported.

Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH)

The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine-substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold. Herein, we report the discovery of 1 (tropifexor, LJN452), a novel and highly potent agonist of FXR. Potent in vivo activity was demonstrated in rodent PD models by measuring the induction of FXR target genes in various tissues. Tropifexor has advanced into phase 2 human clinical trials in patients with NASH and PBC.