Daniel Merk

Therapeutic modulators of peroxisome proliferator-activated receptors (PPAR): a patent review (2008–present)

Introduction: Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. The three known subtypes PPARα, PPARγ and PPARδ have different tissue distribution and play a key role as regulators of glucose and lipid homeostasis as well as in cell proliferation, differentiation and inflammatory responses. They have gained a lot of interest as pharmaceutical targets over the last years and with the antidiabetic thiazolidindiones (TZDs) and the hypolipidemic fibrates, two classes of drugs had entered the market. Early observations of severe adverse events changed the situation in the recent past. Areas covered: Herein the authors summarize recent (2008–present) patent applications concerning PPAR ligands claimed for the use in metabolic disorders as well as patents indicating new applications for modulators of the PPAR subtypes. Expert opinion: Looking at the recent patent activity regarding novel compounds, there have not been real innovations. As major applications for therapeutic PPAR ligands cancer therapy, skin-related disorders and systemic anti-inflammatory therapies might arise in the mid-term future. The known PPAR targeting drugs might see a repurposing for novel indications.

Medicinal chemistry of farnesoid X receptor ligands: from agonists and antagonists to modulators.

The nuclear receptor farnesoid X receptor (FXR) has emerged as a highly promising target in preclinical development in recent years. A significant amount of research has been conducted and, although none has reached clinical use, many synthetic ligands of FXR have been described. This review outlines the available knowledge regarding the medicinal chemistry and SAR of these FXR ligands, and discusses the molecular interactions of the compounds with the FXR ligand-binding domain by interpreting the existing co-crystal structures.

Extending the Structure–Activity Relationship of Anthranilic Acid Derivatives As Farnesoid X Receptor Modulators: Development of a Highly Potent Partial Farnesoid X Receptor Agonist

The ligand activated transcription factor nuclear farnesoid X receptor (FXR) is involved as a regulator in many metabolic pathways including bile acid and glucose homeostasis. Therefore, pharmacological activation of FXR seems a valuable therapeutic approach for several conditions including metabolic diseases linked to insulin resistance, liver disorders such as primary biliary cirrhosis or nonalcoholic steatohepatitis, and certain forms of cancer. The available FXR agonists, however, activate the receptor to the full extent which might be disadvantageous over a longer time period. Hence, partial FXR activators are required for long-term treatment of metabolic disorders. We here report the SAR of anthranilic acid derivatives as FXR modulators and development, synthesis, and characterization of compound 51, which is a highly potent partial FXR agonist in a reporter gene assay with an EC50 value of 8 ± 3 nM and on mRNA level in liver cells.

Anthranilic acid derivatives as novel ligands for farnesoid X receptor (FXR).

Nuclear farnesoid X receptor (FXR) has important physiological roles in various metabolic pathways including bile acid, cholesterol and glucose homeostasis. The clinical use of known synthetic non-steroidal FXR ligands is restricted due to toxicity or poor bioavailability. Here we report the development, synthesis, in vitro activity and structure-activity relationship (SAR) of anthranilic acid derivatives as novel FXR ligands. Starting from a virtual screening hit we optimized the scaffold to a series of potent partial FXR agonists with appealing drug-like properties. The most potent derivative exhibited an EC50 value of 1.5±0.2 μM and 37±2% maximum relative FXR activation. We investigated its SAR regarding polar interactions with the receptor by generating derivatives and computational docking.

Opportunities and Challenges for Fatty Acid Mimetics in Drug Discovery

Fatty acids beyond their role as an endogenous energy source and storage are increasingly considered as signaling molecules regulating various physiological effects in metabolism and inflammation. Accordingly, the molecular targets involved in formation and physiological activities of fatty acids hold significant therapeutic potential. A number of these fatty acid targets are addressed by some of the oldest and most widely used drugs such as cyclooxygenase inhibiting NSAIDs, whereas others remain unexploited. Compounds orthosterically binding to proteins that endogenously bind fatty acids are considered as fatty acid mimetics. On the basis of their structural resemblance, fatty acid mimetics constitute a family of bioactive compounds showing specific binding thermodynamics and following similar pharmacokinetic mechanisms. This perspective systematically evaluates targets for fatty acid mimetics, investigates their common structural characteristics, and highlights demands in their discovery and design. In summary, fatty acid mimetics share particularly favorable characteristics justifying the conclusion that their therapeutic potential vastly outweighs the challenges in their design.

Medicinal Chemistry and Pharmacological Effects of Farnesoid X Receptor (FXR) Antagonists

The nuclear bile acid sensor farnesoid X receptor (FXR) constitutes a rising target for the treatment of a variety of diseases including metabolic disorders, inflammation and certain forms of cancer. While the research on FXR agonists has yielded many compounds and first clinical candidates, only few FXR antagonists have been discovered so far and the knowledge about their in vivo effects is quite narrow. We have evaluated available in vitro and in vivo studies with FXR antagonists as well as FXR knockout models to elucidate a potential pharmacological use of FXR antagonism. To date, the in vitro and in vivo data suggests that FXR inhibition by knockout or the use of antagonists causes beneficial effects on cholesterol metabolism, ameliorates liver toxicity in cholestasis and can reduce the proliferation and migration of some cancer cell lines. Unfortunately, also many disadvantageous effects are connected with FXR antagonists.

Repairing mutated proteins – development of small molecules targeting defects in the cystic fibrosis transmembrane conductance regulator

Introduction: Cystic fibrosis (CF) is the most prevalent, recessively inherited, disease in the western world. It is characterized by gene mutations in CF transmembrane conductance regulator (CFTR), a transmembrane ion channel that is responsible for chloride secretion in the airway passages. Although much is known about the defects in CFTR and the consequences of these mutations, CF therapy currently focuses on the secondary outcomes and symptoms of the disease. However, developments in CFTR modulators may bring about new therapeutic options. Areas covered: The authors discuss CFTR defects, as a molecular basis, before presenting and discussing CFTR modulators including correctors and potentiators. Specifically, the authors review promising CFTR modulators currently in preclinical and clinical development along with their medicinal chemistry and structure–activity relationships (SARs) and their in vitro and in vivo pharmacology. Expert opinion: Although the development of CFTR-targeting agents has little access to structural information from crystal structures, several promising compounds have been discovered so far. Advanced virtual models of CFTR and high-throughput assays have helped the developmental programs. While Ivacaftor, the first of the CFTR potentiators, has now reached clinical use, CFTR corrector development has not been successful thus far. However, intense research of the mutation F508del, the mutation considered the most frequent in CF, could provide new causal treatment options in the future. Furthermore, the eventual synergy with multiple correctors may bring further success. CFTR modulators provide a new personalized therapeutic option where CF therapy is based on the mutations patients carry rather than by simply their symptoms.

Novel prostaglandin receptor modulators: a patent review (2002 – 2012) – part I: non-EP receptor modulators

Introduction: Prostaglandins and their G-protein coupled receptors play numerous physiological and pathophysiological roles especially in inflammation and its resolution. The variety of physiological effects mediated by prostanoids makes prostanoid receptors valuable drug targets and the research on prostaglandin receptor modulators is intensive. Prostaglandin receptor targeting drugs might be beneficial for the treatment of inflammatory, allergic, respiratory and cardiovascular disorders as well as treatment of pain but several novel fields of use such as cancer and ophthalmic diseases have also been found apart from these classical indications. Areas covered: Evaluation of the patent activity over the last decade (2002 – 2012) illustrates many potent and selective modulators of the distinct prostanoid receptors and some novel methods for their use besides the classical indications. By now, some prostaglandin receptor antagonists already have reached clinical development. Expert opinion: Though the structural diversity of compounds targeting prostanoid receptors is not really large, several highly potent agents with favorable properties have been developed. The clinical potential of FP, IP, TP and DP modulators remains to be investigated, while first very promising clinical results are available as far as CRTH2 is concerned.

De Novo Design of Bioactive Small Molecules by Artificial Intelligence

Generative artificial intelligence offers a fresh view on molecular design. We present the first‐time prospective application of a deep learning model for designing new druglike compounds with desired activities. For this purpose, we trained a recurrent neural network to capture the constitution of a large set of known bioactive compounds represented as SMILES strings. By transfer learning, this general model was fine‐tuned on recognizing retinoid X and peroxisome proliferator‐activated receptor agonists. We synthesized five top‐ranking compounds designed by the generative model. Four of the compounds revealed nanomolar to low‐micromolar receptor modulatory activity in cell‐based assays. Apparently, the computational model intrinsically captured relevant chemical and biological knowledge without the need for explicit rules. The results of this study advocate generative artificial intelligence for prospective de novo molecular design, and demonstrate the potential of these methods for future medicinal chemistry.

A Dual Modulator of Farnesoid X Receptor and Soluble Epoxide Hydrolase To Counter Nonalcoholic Steatohepatitis

Nonalcoholic steatohepatitis arising from Western diet and lifestyle is characterized by accumulation of fat in liver causing inflammation and fibrosis. It evolves as serious health burden with alarming incidence, but there is no satisfying pharmacological therapy to date. Considering the diseases multifactorial nature, modulation of multiple targets might provide superior therapeutic efficacy. In particular, farnesoid X receptor (FXR) activation that revealed antisteatotic and antifibrotic effects in clinical trials combined with inhibition of soluble epoxide hydrolase (sEH) as anti-inflammatory strategy promises synergies. To exploit this dual concept, we developed agents exerting partial FXR agonism and sEH inhibitory activity. Merging known pharmacophores and systematic exploration of the structure-activity relationship on both targets produced dual modulators with low nanomolar potency. Extensive in vitro characterization confirmed high dual efficacy in cellular context combined with low toxicity, and pilot in vivo data revealed favorable pharmacokinetics as well as engagement on both targets in vivo.