Zoran Rankovic

From magic bullets to designed multiple ligands

Increasingly, it is being recognised that a balanced modulation of several targets can provide a superior therapeutic effect and side effect profile compared to the action of a selective ligand. Rational approaches in which structural features from selective ligands are combined have produced designed multiple ligands that span a wide variety of targets and target classes. A key challenge in the design of multiple ligands is attaining a balanced activity at each target of interest while simultaneously achieving a wider selectivity and a suitable pharmacokinetic profile. An analysis of literature examples reveals trends and insights that might help medicinal chemists discover the next generation of these types of compounds.

Designing multiple ligands - medicinal chemistry strategies and challenges.

It has been widely recognised over the recent years that parallel modulation of multiple biological targets can be beneficial for treatment of diseases with complex etiologies such as cancer asthma, and psychiatric disease. In this article, current strategies for the generation of ligands with a specific multi-target profile (designed multiple ligands or DMLs) are described and a number of illustrative example are given. Designing multiple ligands is frequently a challenging endeavour for medicinal chemists, with the need to appropriately balance affinity for 2 or more targets whilst obtaining physicochemical and pharmacokinetic properties that are consistent with the administration of an oral drug. Given that the properties of DMLs are influenced to a large extent by the proteomic superfamily to which the targets belong and the lead generation strategy that is pursued, an early assessment of the feasibility of any given DML project is essential.

CNS Drug Design: Balancing Physicochemical Properties for Optimal Brain Exposure

The human brain is a uniquely complex organ, which has evolved a sophisticated protection system to prevent injury from external insults and toxins. Designing molecules that can overcome this protection system and achieve optimal concentration at the desired therapeutic target in the brain is a specific and major challenge for medicinal chemists working in CNS drug discovery. Analogous to the now widely accepted rule of 5 in the design of oral drugs, the physicochemical properties required for optimal brain exposure have been extensively studied in an attempt to similarly define the attributes of successful CNS drugs and drug candidates. This body of work is systematically reviewed here, with a particular emphasis on the interplay between the most critical physicochemical and pharmacokinetic parameters of CNS drugs as well as their impact on medicinal chemistry strategies toward molecules with optimal brain exposure. A summary of modern CNS pharmacokinetic concepts and methods is also provided.

A novel linker strategy for solid-phase synthesis

Abstract The REM resin for solid phase synthesis is described. Its use is illustrated by preparing a small array of tertiary amines using a Hofmann elimination reaction. No functional group is required for linking these compounds onto the resin other than the amine constructed during the synthesis.

A novel series of positive modulators of the AMPA receptor: discovery and structure based hit-to-lead studies.

Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor.

Structure based evolution of a novel series of positive modulators of the AMPA receptor

Starting from compound 1, we utilized biostructural data to successfully evolve an existing series into a new chemotype with a promising overall profile, exemplified by 19.

Positive allosteric modulators of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor.

L-glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays a fundamental role in the control of motor function, cognition and mood. The physiological effects of glutamate are mediated through two functionally distinct receptor families. While activation of metabotropic (G-protein coupled) glutamate receptors results in modulation of neuronal excitability and transmission, the ionotropic glutamate receptors (ligand-gated ion channels) are responsible for mediating the fast synaptic response to extracellular glutamate.

Fragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors.

Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivatives which were profiled in the primary ROCK-I IMAP assay. Compounds 23A and 23E were selected as fragment optimized hits for further profiling. Compound 23A has similar ROCK-1 affinity, potency and cell based efficacy to the first generation ROCK inhibitors, however, it has a superior PK profile in C57 mouse. Compound 23E demonstrates the feasibility of improving ROCK-1 affinity, potency and cell based efficacy for the series, however, it has a poor PK profile relative to 23A.

A novel series of positive modulators of the AMPA receptor: structure-based lead optimization.

Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity.

Cathepsin K inhibitors, 2000 – 2004

Cathepsin K is one of eleven cysteine proteases from the papain superfamily known to be expressed in the human genome. Its selective and abundant expression in osteoclasts and critical role in the degradative phase of bone remodelling suggests that selective inhibition of cathepsin K may provide an effective therapy for the treatment of osteoporosis. This hypothesis has generated considerable interest over the past decade in the development of selective cathepsin K inhibitors. Around 190 cathepsin K-related patent applications have been filed since its discovery in rabbit osteoclasts a decade ago; half of which were published in the last two years, indicating the rapidly increasing level of activity in the field. Small-molecule cathepsin K inhibitors have been reported to show efficacy in animal models of osteoporosis. Most recently, the disclosure from Novartis of the successful completion of Phase IIa trials is likely to attract even greater attention to the target. In addition to a role in bone remodelling, evidence supporting the involvement of cathepsin K in spontaneous rupture of atherosclerotic plaque, leading to arterial thrombosis and potentially fatal myocardial infarction, has also been reported recently. This review is focused on recent advances in the development of specific cathepsin K inhibitors, based on the patent literature from January 2000 to June 2004. Given that rapid advances in this period are directly attributable to the availability of crystallographic data, biostructural information related to key enzyme/inhibitor interactions is also briefly summarised.