Patrizio Mattei

Pharmacological Promiscuity: Dependence on Compound Properties and Target Specificity in a Set of Recent Roche Compounds

What parameters determine promiscuity? A compounds potential for promiscuity (pharmacological activity at multiple targets) may be influenced by molecular parameters such as ionization state, lipophilicity, and molecular weight. In an analysis of recent Roche compounds we found that a positive charge is an important determinant for potential promiscuity; aminergic activity was found to be the main reason for overt promiscuity.

An orally active chemokine receptor CCR2 antagonist prevents glomerulosclerosis and renal failure in type 2 diabetes

The progression of diabetic nephropathy is associated with an infiltration of macrophages expressing different phenotypes. As classically activated chemokine receptor CCR2+ macrophages are thought to drive tissue inflammation and remodeling, we tested whether blocking CCR2 could reduce intrarenal inflammation and prevent glomerulosclerosis in type 2 diabetes. This was achieved with RO5234444, an orally active small-molecule CCR2 antagonist that blocks ligand binding, its internalization, and monocyte chemotaxis. Male type 2 diabetic db/db mice were uninephrectomized to increase glomerular hyperfiltration to accelerate the development of glomerulosclerosis. From 16 weeks until killing at 24 weeks of age, mice were chow fed with or without admixed antagonist to achieve a trough plasma concentration above IC50 for binding in the mouse. CCR2 blockade reduced circulating monocyte levels, but did not affect total leukocyte or neutrophil numbers, and was associated with a reduction in the number of macrophages and apoptotic podocytes in the glomerulus. This treatment resulted in a higher total number of podocytes, less glomerulosclerosis, reduced albuminuria, and a significantly improved glomerular filtration rate. This successful pre-clinical trial suggests that this antagonist may now be ready for testing in humans with the nephropathy of diabetes mellitus.

Molecular Recognition of Ligands in Dipeptidyl Peptidase IV

The serine protease dipeptidyl peptidase IV (DPP-IV) is a clinically validated target for the treatment of type II diabetes and has received considerable interest from the pharmaceutical industry over the last years. Concomitant with a large variety of published small molecule DPP-IV inhibitors almost twenty co-crystal structures have been released to the public as of May 2006. In this review, we discuss the structural characteristics of the DPP-IV binding site and use the available X-ray information together with published structure-activity relationship data to identify the molecular interactions that are most important for tight enzyme-inhibitor binding. Optimized interactions with the two key recognition motifs, i.e. the lipophilic S1 pocket and the negatively charged Glu 205/206 pair, result in large gains in binding free energy, which can be further improved by additional favorable contacts to side chains that flank the active site. First examples show that the lessons learned from the X-ray structures can be successfully incorporated into the design of novel DPP-IV inhibitors.

A Real-World Perspective on Molecular Design.

We present a series of small molecule drug discovery case studies where computational methods were prospectively employed to impact Roche research projects, with the aim of highlighting those methods that provide real added value. Our brief accounts encompass a broad range of methods and techniques applied to a variety of enzymes and receptors. Most of these are based on judicious application of knowledge about molecular conformations and interactions: filling of lipophilic pockets to gain affinity or selectivity, addition of polar substituents, scaffold hopping, transfer of SAR, conformation analysis, and molecular overlays. A case study of sequence-driven focused screening is presented to illustrate how appropriate preprocessing of information enables effective exploitation of prior knowledge. We conclude that qualitative statements enabling chemists to focus on promising regions of chemical space are often more impactful than quantitative prediction.

Discovery of carmegliptin: A potent and long-acting dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

Design, synthesis, and SAR are described for a class of DPP-IV inhibitors based on aminobenzo[a]quinolizines with non-aromatic substituents in the S1 specificity pocket. One representative thereof, carmegliptin (8p), was chosen for clinical development. Its X-ray structure in complex with the enzyme and early efficacy data in animal models of type 2 diabetes are also presented.

Systemic bile acid sensing by G protein‐coupled bile acid receptor 1 (GPBAR1) promotes PYY and GLP‐1 release

Nutrient sensing in the gut is believed to be accomplished through activation of GPCRs expressed on enteroendocrine cells. In particular, L‐cells located predominantly in distal regions of the gut secrete glucagon‐like peptide 1 (GLP‐1) and peptide tyrosine‐tyrosine (PYY) upon stimulation by nutrients and bile acids (BA). The study was designed to address the mechanism of hormone secretion in L‐cells stimulated by the BA receptor G protein‐coupled bile acid receptor 1 (GPBAR1).

Aryl- and heteroaryl-substituted aminobenzo[a]quinolizines as dipeptidyl peptidase IV inhibitors.

Synthesis and SAR are described for a structurally distinct class of DPP-IV inhibitors based on aminobenzo[a]quinolizines bearing (hetero-)aromatic substituents in the S1 specificity pocket. The m-(fluoromethyl)-phenyl derivative (S,S,S)-2g possesses the best fit in the S1 pocket. However, (S,S,S)-2i, bearing a more hydrophilic 5-methyl-pyridin-2-yl residue as substituent for the S1 pocket, displays excellent in vivo activity and superior drug-like properties.

ROCK: the Roche medicinal chemistry knowledge application – design, use and impact

Medicinal chemistry is a complex science that lies at the interface of many fields of research and at the very heart of drug discovery, with property relationships based on chemical structure at its core. It is clear that the effective capture and dissemination of medicinal chemistry knowledge and experience will be a key differentiator among pharmaceutical organizations and crucial for the future success in delivering effective and safe drug candidates. Therefore, in 2005 we developed ROCK (Roche medicinal chemistry knowledge), an internal user-friendly and peer-reviewed Wiki-like application to capture, browse and search tacit knowledge, key discoveries and property effects related to chemical structure, which is used as a primary source for addressing challenges faced in drug design.

Aminothiazole Derivatives as Neuropeptide Y5 Receptor Ligands: Finding the Balance between Affinity and Physicochemical Properties

Neuropetide Y is a peptide of 36 amino acids that is widely distributed in the central and peripheral nervous systems. It mediates a number of physiological effects through its various receptor subtypes. Studies in animals have shown that neuropeptide Y is a powerful stimulus of food intake, and it has been demonstrated that the activation of neuropeptide Y5 (NPY5) receptors results in hyperphagia and decreased thermogenesis. Therefore, compounds that antagonize neuropeptide Y at the Y5 receptor subtype might represent an approach to the treatment of eating disorders such as obesity and hyperphagia. Although it has been suggested that the antagonism of the NPY5 receptor does have a major effect on feeding in rats, there is evidence to support the NPY receptor system in humans as a valuable target for the treatment of metabolic disorders. In the course of a medicinal chemistry program designed to identify novel NPY5 receptor antagonists, thiazole derivatives had been described as interesting scaffolds. Our research group previously reported specific substitution patterns on the thiazole scaffold that proved favorable for the compounds to bind the NPY5 receptor with IC50 values in the low nanomolar range, yet these molecules also had poor physicochemical properties. However, a favorable C=O···S interaction was identified that yielded promising, potent thiazole derivatives. As this scaffold offers ample opportunities for optimization, we turned our interest toward the influence of the nature and length of the linker that connects the thiazole to the sulfonamide moiety, and thus the potential of the resulting compounds to function as antagonists of the NPY5 receptor (Scheme 1). As mentioned above, low solubility was identified as a major disadvantage of these thiazole compounds. Therefore, an optimization cycle was added to improve the physicochemical property profile. This was monitored by measuring solubility and permeability by using the parallel artificial membrane permeation assay (PAMPA). A correlation analysis of pIC50 values and physicochemical properties was carried out to determine whether these two parameters could be optimized independently, or if the optimization of affinity would simultaneously yield an inferior (or superior) physicochemical profile. The results indicated that solubility and membrane permeability were positively correlated, whereas no direct correlation between pIC50 and solubility/membrane permeability was observed (Table 1). However, a principal components analysis

Discovery and optimisation of 1-hydroxyimino-3,3-diphenylpropanes, a new class of orally active GPBAR1 (TGR5) agonists.

A series of non-steroidal GPBAR1 (TGR5) agonists was developed from a hit in a high-throughput screening campaign. Lead identification efforts produced biphenyl-4-carboxylic acid derivative (R)-22, which displayed a robust secretion of PYY after oral administration in a degree that can be correlated with the unbound plasma concentration. Further optimisation work focusing on reduction of the lipophilicity provided the 1-phenylpiperidine-4-carboxylic acid derivative (R)-29 (RO5527239), which showed an improved secretion of PYY and GLP-1, translating into a significant reduction of postprandial blood glucose excursion in an oral glucose tolerance test in DIO mice.