Andreas Verras

Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl-1H-benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors

Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging SNAr reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure-activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1.

Discovery of Chromane Propionic Acid Analogues as Selective Agonists of GPR120 with in Vivo Activity in Rodents

GPR120 (FFAR4) is a fatty acid sensing G protein coupled receptor (GPCR) that has been identified as a target for possible treatment of type 2 diabetes. A selective activator of GPR120 containing a chromane scaffold has been designed, synthesized, and evaluated in vivo. Results of these efforts suggest that chromane propionic acid 18 is a suitable tool molecule for further animal studies. Compound 18 is selective over the closely related target GPR40 (FFAR1), has a clean off-target profile, demonstrates suitable pharmacokinetic properties, and has been evaluated in wild-type/knockout GPR120 mouse oGTT studies.

Discovery and Pharmacology of a Novel Class of Diacylglycerol Acyltransferase 2 Inhibitors

DGAT2 plays a critical role in hepatic triglyceride production, and data suggests that inhibition of DGAT2 could prove to be beneficial in treating a number of disease states. This article documents the discovery and optimization of a selective small molecule inhibitor of DGAT2 as well as pharmacological proof of biology in a mouse model of triglyceride production.

Discovery of Triazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys

Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

Protein dynamics and imidazole binding in cytochrome P450 enzymes

P450 (cytochrome P450) enzymes have major roles in the biosynthesis of endogenous factors such as steroids and eicosanoids, in the termination of the action of endogenous factors such as retinoic acid, in the metabolism of most drugs and xenobiotics and in the generation of toxic and carcinogenic products. Understanding the determinants of the substrate and inhibitor specificities of these enzymes is important for drug design. The crystallographic analysis of the deformability of two bacterial P450 active sites associated with the binding of azole (a class of inhibitors with an imidazole or triazole ring that co-ordinates to the haem iron) inhibitors described in the present study illustrates the importance of protein conformational malleability in the binding of imidazole derivatives.

Chapter 10 Cytochrome P450 Enzymes: Computational Approaches to Substrate Prediction

Publisher Summary This chapter discusses the P450 structural information gleaned over the last 20 years from crystallography and homology modeling, structure-based approaches predating structural information, and new approaches to P450 metabolite prediction. The studies that have been conducted of in silico screening of compounds against P450 enzymes have employed pharmacophore and 3D-QSAR methods. The majority of docking algorithms in use today target single enzyme active sites instead of an ensemble. These enzymes are also considered as rigid to allow for quick screening of thousands of compounds. After pharmacophore modeling, molecular dynamics methods are most often employed in predicting P450 metabolism. While this method has the advantages of using an ensemble of structures, the ability to reproduce protein flexibility, and quantify reactive geometries necessary for oxidation, compared to geometries resulting in uncoupled or inactive orientations, it is extremely time consuming.

Informing the Selection of Screening Hit Series with in Silico Absorption, Distribution, Metabolism, Excretion, and Toxicity Profiles

High-throughput screening (HTS) has enabled millions of compounds to be assessed for biological activity, but challenges remain in the prioritization of hit series. While biological, absorption, distribution, metabolism, excretion, and toxicity (ADMET), purity, and structural data are routinely used to select chemical matter for further follow-up, the scarcity of historical ADMET data for screening hits limits our understanding of early hit compounds. Herein, we describe a process that utilizes a battery of in-house quantitative structure-activity relationship (QSAR) models to generate in silico ADMET profiles for hit series to enable more complete characterizations of HTS chemical matter. These profiles allow teams to quickly assess hit series for desirable ADMET properties or suspected liabilities that may require significant optimization. Accordingly, these in silico data can direct ADMET experimentation and profoundly impact the progression of hit series. Several prospective examples are presented to substantiate the value of this approach.

Discovery of Spirocyclic Aldosterone Synthase Inhibitors as Potential Treatments for Resistant Hypertension.

Herein we report the discovery and hit-to-lead optimization of a series of spirocyclic piperidine aldosterone synthase (CYP11B2) inhibitors. Compounds from this series display potent CYP11B2 inhibition, good selectivity versus related CYP enzymes, and lead-like physical and pharmacokinetic properties.