ABSTRACT
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.
Subject(s)
Benzothiazoles/pharmacology , Cholestasis/drug therapy , Isoxazoles/pharmacology , Non-alcoholic Fatty Liver Disease/drug therapy , Receptors, Cytoplasmic and Nuclear/agonists , Administration, Oral , Animals , Benzothiazoles/therapeutic use , Biological Availability , Dogs , Drug Evaluation, Preclinical/methods , Fibroblast Growth Factors/genetics , Gene Expression Regulation/drug effects , Humans , Isoxazoles/therapeutic use , Male , Microsomes, Liver/drug effects , Piperidines/chemistry , Rats, Sprague-Dawley , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , Structure-Activity Relationship , Triglycerides/bloodABSTRACT
The aim of the present study was to determine whether Cremophor EL is a suitable surfactant that can be routinely applied to pharmacokinetic (PK) studies in early drug discovery without influencing the intrinsic PK characteristics of the new chemical entities (NCEs). Cremophor EL, a polyoxyl 35 castor oil, has been used as a solubilization aid for water-insoluble compounds in pre-clinical drug discovery. The effect of Cremophor EL on the PK properties of NCEs was examined in seven structurally diverse discovery compounds after intravenous administration. Significant effects of Cremophor EL on plasma volume of distribution (Vss) and plasma clearance (CL) were observed in compounds with moderate to high Vss or CL. The plasma Vss decreased more than 2-fold and the Vss binning category decreased by one unit (e.g. from moderate to low Vss) in 6 of 7 test compounds. Two to five-fold reduction of CL was observed with these 6 compounds. Effect on the terminal half-life (T1/2) was minimal. Using one of these 7 NCEs, concentration dependent effect of Cremophor EL in the vehicle was also determined. Higher percentage of Cremophor EL in vehicle resulted in progressively increased alterations on the plasma CL and Vss. Taken together, these findings indicated that Cremophor EL altered the intrinsic PK properties of these discovery compounds in a concentration dependent manner.
Subject(s)
Chemistry, Pharmaceutical , Glycerol/analogs & derivatives , Pharmaceutical Preparations/chemistry , Solvents/chemistry , Administration, Topical , Animals , Drug Evaluation, Preclinical , Glycerol/chemistry , Half-Life , Male , Mice , Mice, Inbred BALB C , Pharmaceutical Preparations/blood , Rats , Rats, Sprague-DawleyABSTRACT
Successful drug discovery relies on the selection of drug candidates with good in vivo pharmacokinetic (PK) properties as well as appropriate preclinical efficacy and safety profiles. In vivo PK profiling is often a bottleneck in the discovery process. In this review, we focus on the tiered in vivo PK approaches implemented at the Genomics Institute of the Novartis Research Foundation (GNF), which includes snapshot PK, rapid PK and full PK studies. These in vivo PK approaches are well integrated within discovery research, allow tremendous flexibility and are highly efficient in supporting the diverse needs and increasing demand for in vivo profiling. The tiered in vivo PK studies expedite compound profiling and help guide the selection of more desirable compounds into efficacy models and for progression into development.
Subject(s)
Drug Design , Models, Biological , Pharmacokinetics , Animals , Drug Discovery/methods , Drug Evaluation, Preclinical/methods , Humans , Pharmaceutical Preparations/metabolismABSTRACT
Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.