Jörg Keldenich

New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease

The vast majority of the world population is infected with at least one member of the human herpesvirus family. Herpes simplex virus (HSV) infections are the cause of cold sores and genital herpes as well as life-threatening or sight-impairing disease mainly in immunocompromized patients, pregnant women and newborns. Since the milestone development in the late 1970s of acyclovir (Zovirax), a nucleosidic inhibitor of the herpes DNA polymerase, no new non-nucleosidic anti-herpes drugs have been introduced. Here we report new inhibitors of the HSV helicase-primase with potent in vitro anti-herpes activity, a novel mechanism of action, a low resistance rate and superior efficacy against HSV in animal models. BAY 57-1293 (N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide), a well-tolerated member of this class of compounds, significantly reduces time to healing, prevents rebound of disease after cessation of treatment and, most importantly, reduces frequency and severity of recurrent disease. Thus, this class of drugs has significant potential for the treatment of HSV disease in humans, including those resistant to current medications.

A physiologic model for simulating gastrointestinal flow and drug absorption in rats.

AbstractPurpose. The development of a physiologically based absorption model for orally administered drugs in rats is described.nMethods. Unlike other models that use a multicompartmental approach, the GI tract is modeled as a continuous tube with spatially varying properties. The mass transport through the intestinal lumen is described via an intestinal transit function. The only substance-specific input parameters of the model are the intestinal permeability coefficient and the solubility in the intestinal fluid. With this physiologic and physicochemical information, the complete temporal and spatial absorption profile can be calculated.nResults. A first performance test using portal concentration data published in the literature yielded an excellent agreement between measured and simulated temporal absorption profiles in the portal vein. Furthermore, the dose dependence of a compound with solubility-limited fraction dose absorbed in rats (chlorothiazide) could be adequately described by the model.nConclusions. The continuous absorption model is well suited to simulate drug flow and absorption in the GI tract of rats.

Multilamellar liposomes and solid-supported lipid membranes (TRANSIL): screening of lipid-water partitioning toward a high-throughput scale.

AbstractPurpose. Lipid-water partitioning of 187 pharmaceuticals has been assessed with solid-supported lipid membranes (TRANSIL) in microwell plates and with multilamellar liposomes for a data comparison. The high-throughput potential of the new approach was evaluated.nMethods. Drugs were incubated at pH 7.4 with egg yolk lecithin membranes either on a solid support (TRANSIL beads) or in the form of multilamellar liposomes. Phase separation of lipid and water phase was achieved by ultracentrifugation in case of liposomes or by a short filtration step in case of solid-supported lipid membranes.nResults. Lipid-water partitioning data of both approaches correlate well without systematic deviations in the investigated lipophilicity range. The solid-supported lipid membrane approach provides high-precision data in an automated microwell-plate setup. The lipid composition of the solid-supported lipid membranes was varied to study the influence of membrane change on lipid-water partitioning. In addition, pH-dependent measurements have been performed with minimal experimental effort.nConclusions. Solid-supported lipid membranes represent a valuable tool to determine physiologically relevant lipid-water partitioning data of pharmaceuticals in an automated setup and is well suited for high-throughput data generation in lead optimization programs.

Solid-Supported Biomolecules on Modified Silica Surfaces—A Tool for Fast Physicochemical Characterization and High-Throughput Screening

Biofunctionalization for a wide variety of applications can be achieved by coating silica surfaces with biomolecules such as lipids or proteins. However, specific surface optimization of the inorganic SiO2 is necessary to achieve biocompatible surfaces. Surface shielded porous silica beads can be non-covalently coated with a single lipid bilayer. The lipids retain their fluidity in this handy solid-supported system, perfectly mimicking the soft-surface properties of cellular membranes. A supramolecular architecture can also be used for functional immobilization of membrane proteins: An artificial cytosolic compartment can be created with the aid of polymers; coating by lipid membranes and integration of membrane proteins results in a solid-supported biofunctional cellular surface. Another surface modification enables a direct immobilization of human serum albumin (HSA) molecules onto silica surfaces. The HSA on this otherwise passivated surface provides a convenient material for the investigation of unspecific protein binding of pharmaceuticals on a high-throughput scale.

Discovery of Molidustat (BAY 85‐3934): A Small‐Molecule Oral HIF‐Prolyl Hydroxylase (HIF‐PH) Inhibitor for the Treatment of Renal Anemia

Small‐molecule inhibitors of hypoxia‐inducible factor prolyl hydroxylases (HIF‐PHs) are currently under clinical development as novel treatment options for chronic kidney disease (CKD) associated anemia. Inhibition of HIF‐PH mimics hypoxia and leads to increased erythropoietin (EPO) expression and subsequently increased erythropoiesis. Herein we describe the discovery, synthesis, structure–activity relationship (SAR), and proposed binding mode of novel 2,4‐diheteroaryl‐1,2‐dihydro‐3H‐pyrazol‐3‐ones as orally bioavailable HIF‐PH inhibitors for the treatment of anemia. High‐throughput screening of our corporate compound library identified BAY‐908 as a promising hit. The lead optimization program then resulted in the identification of molidustat (BAYu200585‐3934), a novel small‐molecule oral HIF‐PH inhibitor. Molidustat is currently being investigated in clinical phaseu2005III trials as molidustat sodium for the treatment of anemia in patients with CKD.