Richard Morphy

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.

Selectively Nonselective Kinase Inhibition: Striking the Right Balance

Protein kinases have become the second most exploited group of drug targets after G-protein-coupled receptors (GPCRs), accounting for 30% of drug discovery projects at many pharmaceutical companies with dozens of compounds in clinical development. Most early kinase inhibitors exhibited poor selectivity between kinases, and the trend in recent years has been toward ever more selective inhibitors in an attempt to minimize the risk of side effects. The risk with highly selective inhibitors is that their efficacy for treating complex diseases like cancer might be compromised by the redundancies in signaling pathways. The increasing interest in multitarget drug discovery (MTDD) stems froma belief that modulating more than one target can provide superior efficacy and safety profiles compared to single target drugs. Currently, there are two contrasting MTDD philosophies. The first involves combining agents that are selective for a single target to achieve an additive or synergistic effect. The second involves discovering agents that are simultaneously capable of addressing two or more targets. Although this perspective focuses primarily on the latter, the advantages and disadvantages of both approaches will be highlighted. Very few drugs are truly selective for a single target, and in reality most biologically active small molecules have a degree of promiscuity by their very nature. Many clinically useful drugs are now known to have multiple activities, but most of these multitarget drugs (MTDs) were discovered serendipitously and their mechanisms of action were only established retrospectively. The deliberate and prospective design of ligands that act in a “selectively nonselective” manner on multiple targets of therapeutic interest is an emerging trend in drug discovery. Increasing numbers of these so-called designed multiple ligands (DMLs) are being reported in the medicinal chemistry literature. In particular, identifying multikinase inhibitors (MKIs) with specific multiple activity profiles is currently an area of great interest in the pharmaceutical industry, especially for the treatment of cancer. Five years ago there were few examples of DMLs in the medicinal chemistry literature for kinase targets, but the period since has witnessed an explosive growth in interest in this area. Marketed MKI drugs vary with respect to the number of kinases they are known to inhibit, with some inhibiting only a small number of kinases, whereas others appear to be highly promiscuous. These apparent differences in selectivity are to an extent influenced by the amount of selectivity screening that has been performed,with some inhibitors appearing to be more promiscuous simply on the basis of having been profiled more rigorously. As the title of this Perspective delineates, the aim for themedicinal chemistworking in theMKI field should be to strike the right balance between the nonselectivity (promiscuity) that may be required for efficacy and the selectivity that is required for safety. At present it is difficult to intentionally design aMKIwith activity only at the kinases of interest, but increasingly rational and elegant medicinal chemistry approaches are being applied to solving this difficult problem. This Perspective aims to capture the current state of the art and to explore the future challenges and strategies in this area. The terminology used herein, illustrated using known inhibitors, is summarized in Figure 1.

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.

Resin-immobilised benzyl and aryl vinyl sulfones: New versatile traceless linkers for solid-phase organic synthesis

Abstract New polystyrene-based resins containing benzyl and aryl vinyl sulfone groups are described. The vinyl sulfone group reacts efficiently with 2° amines, via conjugate addition, and the resin-bound 3° amine products can be quatermised through alkylation. Subsequent deamination to give 3° amines and the regenerated vinyl sulfone occurs in moderate to good yield. Both systems can be recycled and show moderate stability to acids and high stability to nucleophiles including Grignard reagents.

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.

Optimisation of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors

Rho kinase is an important target implicated in a variety of cardiovascular diseases. Herein, we report the optimisation of the fragment derived ATP-competitive ROCK inhibitors 1 and 2 into lead compound 14A. The initial goal of improving ROCK-I potency relative to 1, whilst maintaining a good PK profile, was achieved through removal of the aminoisoquinoline basic centre. Lead 14A was equipotent against both ROCK-I and ROCK-II, showed good in vivo efficacy in the spontaneous hypertensive rat model, and was further optimised to demonstrate the scope for improving selectivity over PKA versus hydroxy Fasudil 3.

The identification, and optimisation of hERG selectivity, of a mixed NET/SERT re-uptake inhibitor for the treatment of pain

Hit compound 1, a selective noradrenaline re-uptake transporter (NET) inhibitor was optimised to build in potency at the serotonin re-uptake transporter (SERT) whilst maintaining selectivity against the dopamine re-uptake transporter (DAT). During the optimisation of 1 it became clear that selectivity against the Kv11.1 potassium ion channel (hERG) was also a parameter for optimisation within the series. Discrete structural changes to the molecule as well as a lowering of global cLogP successfully increased the hERG selectivity to afford compound 11 m, which was efficacious in a mouse model of inflammatory pain, complete Freunds adjuvant (CFA) induced thermal hyperalgesia and a rat model of neuropathic pain, spinal nerve ligation (SNL) induced mechanical allodynia.

Multi-target Drugs

Publisher Summary There are three distinctly different approaches to multitarget therapy. Clinicians have treated unresponsive patients by combining therapeutic mechanisms with cocktails of drugs. Historically, the compounds produced by medicinal chemists were screened by in vivo pharmacologists in whole animal models of disease. This approach provided a means to identify, in a single test, compounds that exhibited a rare combination of desirable pharmacokinetic (PK) and pharmacodynamic (PD) properties. Agents that modulate multiple targets simultaneously (polypharmacology) have the potential to enhance efficacy or improve safety relative to drugs that address only a single target. Across the pharmaceutical industry, the fixed dose combination (FDC) approach is increasingly providing an attractive opportunity for enhancing R&D output. Several drugs currently on the market have been found to have activity at more than one target. Compared to optimizing the balance of affinities and the wider selectivity, an even greater challenge for medicinal chemists when confronted with the challenge of designing multiple ligands is to obtain physicochemical and PK properties consistent with developing an oral drug. The influence of physicochemical properties on the PK behavior of orally administered drugs has been the subject of intense interest over the past few years. The field of multiple ligands will present future generations of medicinal chemists with many challenges, but also numerous opportunities to discover a range of new and superior medicines.