Current Pharmaceutical Design - Volume 15, Issue 6, 2009

Structural manipulation of already marketed drugs, or in general, of known biologically active compounds as a means to get novel drug candidates with improved profiles constitutes a widespread practice in medicinal chemistry. In most cases, from this approach arise novel molecules with a degree of structural complexity similar to that of the parent compound and containing a single pharmacophoric moiety aimed at hitting a single biological target. Another way to get access to novel drug candidates from known drugs that is attracting an ever-expanding interest involves the combination of more than one identical or different pharmacophores rather than the structural modificacion of a single one. This approach results in, obviously more complex, dimeric or hybrid drug candidates with significantly distinct pharmacological profiles relative to the monomeric parent compounds from which they were designed. Thus, combination into a single framework of carefully selected different pharmacophoric moieties can endow the resulting hybrid molecule with the ability to interact with different biological targets, thereby leading to a sequential interference at different levels of a given pathogenic pathway or to a series of complementary pharmacological effects, and, consequently to an enhanced efficiency in the management of that particular disease. Also, hybrid and dimeric drug candidates can be rationally designed to provide multivalent interactions with biological targets having more than one binding site or even with targets which are themselves oligomeric, thus affording a dramatically increased affinity. In this issue, the rationale for the design of representative examples of different classes of multivalent dimeric and hybrid drug candidates is discussed, as well as the advantages they provide over their monomeric counterparts in different therapeutic areas.

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.

The multifunctional nature of Alzheimer's disease (AD) provides the logical foundation for the development of an innovative drug design strategy centered on multi-target-directed-ligands (MTDLs). In recent years, the MTDL concept has been exploited to design different ligands hitting different biological targets. Our first rationally designed MTDL was the polyamine caproctamine (1), which provided a synergistic cholinergic action against AD by antagonizing muscarinic M2 autoreceptors and inhibiting acetylcholinesterase (AChE). Lipocrine (7) represented the next step in our research. Due to its ability to inhibit AChE catalytic and non-catalytic functions together with oxidative stress, 7 emerged as an interesting pharmacological tool for investigating the neurodegenerative mechanism underlying AD. Memoquin (9) is a quinonebearing polyamine endowed with a unique multifunctional profile. With its development, we arrived at the proof of concept of the MTDL drug discovery approach. Experiments in vitro and in vivo confirmed its multimodal mechanisms of action and its interaction with different end-points of the neurotoxic cascade leading to AD. More recently, the MTDL approach led to carbacrine (12). In addition to the multiple activities displayed by 7, 12 displayed an interesting modulation of NMDA receptor activity. The pivotal role played by this target in AD pathogenesis suggests that 12 may be a promising new chemical entity in the MTDL gold rush.

The pharmacotherapy of complex pathological states at the cardiovascular level often requires different and complementary pharmacodynamic properties. This is frequently achieved through the administration of “cocktails”, composed by several drugs possessing different mechanisms of action. In the last years, a revision of the “one-compound-onetarget” paradigm led to a wide development of new classes of molecules, possessing more pharmacological targets. Among them, this innovative strategy produced interesting hybrid drugs, with a dual mechanism of action: a) a fundamental and well-established pharmacodynamic profile and b) the release of nitric oxide (NO), playing a pivotal role in the modulation of the function of cardiovascular system, where it induces vasorelaxing and antiplatelet responses. These new pharmacodynamic hybrids present the advantage of adding to a main mechanism of action (for example, cyclooxygenase inhibition, beta-antagonism or ACE-inhibition) also a slow release of NO, useful either to reduce the adverse side effects and/or to improve the effectiveness of the drug. This review presents the chemical features of many examples of NO-releasing hybrids of cardiovascular drugs and explains the pharmacological improvements conferred by the addition of such NO-donor properties.

Ligands selectively targeting β -amyloid in the living brain are promising candidates of therapeutics and early diagnosis tools for Alzheimer's disease. Among the major stages of β -amyloid aggregation, monomers and oligomers are excellent targets to reduce neurotoxic brain damages for prevention of the disease progression, while oligomers and fibrils, abundant in the late stage of the disease, are pathological objectives to develop reliable imaging probes. So far, there have been many efforts to develop a wide variety of monovalent β -amyloid ligands such as thioflavin T, PIB, FDDNP, curcumin, and tramiprosate. However, pathology of Alzheimer's disease is not fully understood yet so that there is currently no cure and further investigations on Alzheimer's disease are needed. For past several years, multivalent β -amyloid ligands have offered an alternative route by enhancing binding affinity of drug candidates. In addition, it has been revealed that not only neurotoxicity due to the protein misfolding but also other factors are involved in the β -amyloid cascade such as oxidative stress, inflammation, metal chelation, and several types of neurotransmitters. Thus, there have been numerous studies to improve binding affinities of single β -amyloid ligands via adopting multivalent effects or to develop drug candidates targeting multiple stages of the pathological cascade. In this review, multivalent and multifunctional β - amyloid ligands and their promising aspects as an alternative approach to Alzheimer's disease are discussed.

Polyvalency in the biological world is defined as the simultaneous binding of multiple ligands to one receptor. Polyvalency can increase the affinity of the polyvalent ligand by 100-1000 fold over the monovalent ligand. Such phenomenon has been employed to design polyvalent toxin inhibitors. Bivalency is a similar approach where two ligands are joined together with a linker to form a homo- or hetero-dimer with an increase in affinity by up to several hundred fold over the monovalent ligand. This review will summarize the recent advancement in designing bivalent inhibitors to be used as antitumour agents. Some dimers (e.g. artemisinin homo-dimer) simply increase the affinity of the monovalent ligands without detailed knowledge of the target. Other dimers are designed with well-characterized targets, for example, jesterone dimer (inhibiting Rel/NF- B) and 3,3'-diindolymethane and their derivatives (inhibiting Akt and NF B). Some dimers are designed based on the high definition structure between ligand and target (e.g. benzodiazepine and daunorubicin interacting with DNA). Heterodimers have also been produced by combining either two different antitumor drugs (e.g. cis-platin/acridine or cis-platin/naphthalimide) or combining one antitumor candidate (artemisinin) with a molecule which can increase the efficacy of the former (transferrin receptor). Finally we will discuss the design of bivalent inhibitors of the P-glycoprotein (ABCB1; MDR or P-gp) to overcome the problem of antitumor resistance.

Recent advances in designing peptide ligands for therapeutic targets are making peptides an attractive alternative to small molecules and proteins. It is now common to see peptides developed with affinities comparable to antibodies and specificities much better than small molecules or antibodies. This is especially true in the case of tumor targeting cytotoxic drugs or targeted diagnostics where peptides can be used as a delivery vehicle for drugs or diagnostics. Moreover, lessons learned from nature in understanding peptide ligands are proving to be useful in designing better antibodies and small molecule therapeutics.

More and more evidences are still accumulating rapidly on the G-protein-coupled-receptors (GPCRs) dimerization/ oligomerization. Such common feature of GPCRs has called extensive attention to both pharmacologists and medicinal chemists for illustration of the pharmacological functions and therapeutic utilities of such receptor complex. Although there is still no clear explanation for the receptor dimerization/oligomerization, a large number of multivalent ligands (MLs) have been designed to target the receptor-dimers/oligomers. Such MLs have gained much acceptance in exploring the receptor complex of dopaminergic, adrenergic, serotoninergic, and opioidic receptor systems, due to the relatively broader experience in recognizing the receptor-dimerization. More and more MLs have also been designed to face GPCRrelated very complex neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD) and schizophrenia, which are not effectively treated by traditional highly selective drugs. Herein, some of the most recent developments in this field, as well as some typical examples of MLs, are highlighted, with a particular focus on GPCRs.

Historically treated as monomeric polypeptides, G protein-coupled receptors (GPCRs) have been shown to exist and function as constitutively formed dimers or oligomers. The quaternary structure of GPCRs may modulate ligand binding properties through allosteric mechanisms offering new opportunities for drug design by exploiting multivalency. In this context, multivalent ligands versus bivalent-ligands, possessing two binding motifs connected by a linker, have been investigated and have revealed striking differences in their functional properties compared to their monovalent counterparts. These bi-functional drugs, which are able to activate the two protomers in a dimer simultaneously, emerge as novel and promising drugs for a variety of multi-factorial diseases. In this review, key requirements for the successful design and synthesis of GPCR multivalent ligands composed of pharmacophores and a linker will be discussed. We will then focus on the 5-HT4 receptor (5-HT4R), whose ligands emerged as promising drugs for a variety of central nervous disorders. Upon description of biochemical and biophysical evidences of 5-HT4R dimerization, we will present the multivalent ligand approach, which was assisted by molecular docking experiments on the 5-HT4R dimer model.