Steven Joseph Berthel

Peptidomimetic compounds that inhibit antigen presentation by autoimmune disease-associated class II major histocompatibility molecules

We have identified a heptapeptide with high affinity to rheumatoid arthritis–associated class II major histocompatibility (MHC) molecules. Using a model of its interaction with the class II binding site, a variety of mimetic substitutions were introduced into the peptide. Several unnatural amino acids and dipeptide mimetics were found to be appropriate substituents and could be combined into compounds with binding affinities comparable to that of the original peptide. Compounds were designed that were several hundred-fold to more than a thousand-fold more potent than the original peptide in inhibiting T-cell responses to processed protein antigens presented by the target MHC molecules. Peptidomimetic compounds of this type could find therapeutic use as MHC-selective antagonists of antigen presentation in the treatment of autoimmune diseases.

Glucokinase activators as new type 2 diabetes therapeutic agents

Background: Small molecule glucokinase activators (GKAs) represent a new strategy to treat type 2 diabetes. Glucokinase (GK) primarily exerts its effect through modulatory actions in the pancreatic β-cells and the liver. It couples insulin secretion in the pancreas with plasma glucose concentration, and improves glucose utilization in the liver, thus affecting two key aspects of glucose homeostasis. Objective and method: To review currently disclosed GKA structures and to classify them based on the key structural features. For this purpose, the data from patent disclosures and publications are used. Also, published in vitro findings on related lead GKAs are used to compare their effect on GK kinetics. Results and conclusion: The most common GKA pharmacophore consists of a center, which can be a carbon or an aromatic ring, and three attachments. Two of these are hydrophobic groups, with at least one of them being an aromatic ring. The third attachment, without exception, consists of an H-bond donor–acceptor pair in the form of a heterocyclic amine, or an N-acyl urea. These structurally diverse GKAs show important differences in their effects on the kinetic properties of GK.

Research and Development of Glucokinase Activators for Diabetes Therapy: Theoretical and Practical Aspects

Glucokinase Glucokinase (GK GK ; EC 2.7.1.1.) phosphorylates and regulates glucose metabolism in insulin-producing pancreatic beta-cells, hepatocytes, and certain cells of the endocrine and nervous systems allowing it to play a central role in glucose homeostasis glucose homeostasis . Most importantly, it serves as glucose sensor glucose sensor in pancreatic beta-cells mediating glucose-stimulated insulin biosynthesis and release and it governs the capacity of the liver to convert glucose to glycogen. Activating and inactivating mutations of the glucokinase gene cause autosomal dominant hyperinsulinemic hypoglycemia and hypoinsulinemic hyperglycemia in humans, respectively, illustrating the preeminent role of glucokinase in the regulation of blood glucose and also identifying the enzyme as a potential target for developing antidiabetic drugs antidiabetic drugs . Small molecules called glucokinase activators (GKAs) glucokinase activators (GKAs) which bind to an allosteric activator allosteric activator site of the enzyme have indeed been discovered and hold great promise as new antidiabetic agents. GKAs increase the enzymes affinity for glucose and also its maximal catalytic rate. Consequently, they stimulate insulin biosynthesis and secretion, enhance hepatic glucose uptake, and augment glucose metabolism and related processes in other glucokinase-expressing cells. Manifestations of these effects, most prominently a lowering of blood glucose, are observed in normal laboratory animals and man but also in animal models of diabetes and patients with type 2 diabetes mellitus (T2DM T2DM ) type 2 diabetes mellitus (T2DM) . These compelling concepts and results sustain a strong R&D effort by many pharmaceutical companies to generate GKAs with characteristics allowing for a novel drug treatment of T2DM.

Novel glucokinase activators: a patent review (2008 – 2010)

Importance of the field: Small molecule glucokinase activators (GKAs) continue to represent a potential strategy to treat type 2 diabetes (T2D). Glucokinase (GK) primarily exerts its effect through modulatory actions in pancreatic β-cells and hepatocytes. It couples insulin secretion in the pancreas with plasma glucose concentration and improves glucose utilization in the liver, thus, affecting two key aspects of glucose homeostasis. There has been an intense interest in GKAs within the pharmaceutical industry ever since the first report of a low molecular mass activator in 2003. The key drivers for this interest are the robust glucose lowering activity observed with GKAs in preclinical T2D animal models and early reports of efficacy in T2D patients. Areas covered in this review: The objective is to review GKA structures disclosed during the 2008 – 2010 period and classify them based on key structural features. For this purpose, only compound data from patent disclosures were used. What the reader will gain: The reader would gain a detailed view of structural diversity of the GKA field disclosed during the review period. Take home message: There continues to be a high level of interest within the pharmaceutical industry in novel GKAs. Several new and highly potent structure types were reported for the first time in the past 3 years. Common features of all of them include a hydrogen bond donor–acceptor pair that makes contact with the backbone CO- and NH- bonds of Arg 63 residue on GK and two hydrophobic groups. During this review period, several GKAs progressed to Phase II clinical testing and the data on their safety and efficacy profiles are eagerly awaited.

7-Phenyl-pyrido[2,3-d]pyrimidine-2,4-diamines: novel and highly selective protein tyrosine phosphatase 1B inhibitors.

High throughput screening of the Roche compound collection led to the identification of diaminopyrroloquinazoline series as a novel class of PTP1B inhibitors. Structural modification of diaminopyrroloquinazoline series resulted in pyrido[2,3-d]pyrimidine-2,4-diamine series which was further optimized to give compounds 5 and 24 as potent, selective (except T-cell phosphatase) PTP1B inhibitors with good mouse PK properties.

Intuitive patent Markush structure visualization tool for medicinal chemists.

A Markush, or generic structure, is a widely used convention in chemical and pharmaceutical patents. The flexibility and complexity of this format, however, preclude an easy understanding and analysis of chemical space. In this paper, an application package called MarVis (Markush Visualization) is introduced to help chemists visualize Markush structures in chemical patents. MarVis can output a report with the Markush structure showing the query substructure and also an R-group table of all the possible R-groups described in the patent. MarVis also has a unique interactive interface that allows chemists to explore and zoom in the chemical space to find a subset of interest. SMILES, with minimal extensions, was used to facilitate a variety of patent Markush structure studies.

[4+2] Cycloaddition Reactions of Indole Derivatives

A review with 141 references on [4+2] cycloaddition reactions involving the indole nucleus.

Potent, selective MCH-1 receptor antagonists.

This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.

Identification of RO4597014, a Glucokinase Activator Studied in the Clinic for the Treatment of Type 2 Diabetes.

To resolve the metabolite redox cycling associated with our earlier clinical compound 2, we carried out lead optimization of lead molecule 1. Compound 4 showed improved lipophilic ligand efficiency and demonstrated robust glucose lowering in diet-induced obese mice without a liability in predictive preclinical drug safety studies. Thus, it was selected as a clinical candidate and further studied in type 2 diabetic patients. Clinical data suggests no evidence of metabolite cycling, which is consistent with the preclinical profiling of metabolism.

Identification of phenyl-pyridine-2-carboxylic acid derivatives as novel cell cycle inhibitors with increased selectivity for cancer cells.

Ro 41-4439, a phenyl-pyridine-2-carboxylic acid derivative, was identified by a cell-based screening approach that exploits the differences between normal and cancer cells in their sensitivity to cytotoxic agents. This compound showed low micromolar antiproliferative activity and cytotoxicity against a broad panel of human cancer cell lines in vitro, and over 10-fold selectivity to cancer cells when tested in parallel with a panel of proliferating normal human cells. Cytotoxicity of Ro 41-4439 is due to arrest of cell cycle progression in mitosis followed by induction of apoptosis. Four-week treatment of nude mice bearing established mammary tumor xenografts (MDA-MB-435) with well-tolerated doses of the compound showed 73% inhibition of tumor growth. Limited exploration of structure–activity relationships involving side chain length, and aryl and pyridine rings allowed for the identification of more potent analogs.