DrugDiscovery-DML.ppt

1、Designed Multiple Ligands. An Emerging Drug Discovery Paradigm,Reference: Journal of Medicinal Chemistry 2005, Vol. 48, No. 21, 6523-6543,Introduction,Drug discovery for the past century:,Potential compounds,Animal models,Clinical trials,Marketing,Then to today:,“one-target, one-disease”,In the futu

2、re, what will happen?,Aim: developing agents that modulate multiple targets simultaneously,Figure 1. Three main clinical scenarios for multitarget therapy.,For A: poor patient compliance For B: weak dose flexibility and more cost treatment and highly complex PK/PD For C: a profoundly different risk-

3、benefit profile,More difficult to adjust the ratio of activities at the different targets, but all these happen in the earlier stages of drug discovery process. Another advantage is a lower risk of drug-drug interactions compared to cocktails or multicomponent drugs.,For C: a profoundly different ri

4、sk-benefit profile,Designed multiple ligands (DMLs) Compounds whose multiple biological profile is rationally designed to address a particular disease, with the overall goal of enhancing efficacy and/or improving safety.,Ligands that possess significant activity at irrelevant targets should not be r

5、egarded as DMLs but rather as “nonselective” ligands, since undesirable cross-reactivity frequently leads to deleterious side effects.,For example,aspirin,selective cyclooxygenase-2 (COX-2) inhibitors,Nonsteroidal anti-inflammatory drugs (NSAIDs) nonselective agent,Dual COX-2 / 5-lipoxygenase (5-LOX

6、) inhibitors,Strategies for Designed Multiple Ligands,Classification of Designed Multiple Ligands,Figure 3. DML continuum. Ligands vary greatly in the degree of merger of the frameworks (and the underlying pharmacophores) of the selective ligands used as the starting points.,Knowledge-Based “Designi

7、ng In” Approaches,Conjugates,The covalent linking of selective adenosine A1 and A3 agonists by Jacobson et al. using a rigid ethynyl-based spacer led to conjugates with the desired dual activity 2. Evaluation of these conjugates in models of myocardial ischemia confirmed that activation of both A1 a

8、nd A3 receptor subtypes resulted in a cardioprotective effect that is significantly greater than that induced by activation of either receptor individually.,An ester-based linker, designed to be cleaved by plasma esterases to release two individual drugs that then act independently,The ibuprofen der

9、ivative 5,NO-aspirin 4 (NCX-4016),Fused DMLs,Non-peptide gastrin antagonist 6 (L-365,260) onto the peptide N-acetyl-CCK-7,The only realistic option may be fusion of the frameworks by exploiting tolerant positions in each component.,Buckholder et al. desired a dual NK1/NK2 ligand and attempted to ach

10、ieve balanced activity. Whereas the directly analogous 2-methoxy derivative was only 4-fold more active, the 3,4,5-trimethoxy derivative had much improved NK1 affinity.,Merged DMLs,matrix metalloprotease-1 (MMP-1) (16) and cathepsin L (Cat L) inhibitors (17),The use of two warheads positioned at eit

11、her end, enabled the barrier between the metalloprotease and cysteine protease families to be overcome in 18,DMLs from Screening Approaches,Screening relies largely on serendipity to generate a hit compound with multiple activity.,Screening can add particular value if there is a lack of selective li

12、gands for the targets of interest and little knowledge of the individual SARs. screening can deliver novel and unexpected chemotypes, as well as sometimes providing hits for unusual target combinations that span unrelated receptor families.,The potential of using “old drugs” as a starting point for

13、a DML project has also been demonstrated. For example, the 5-HT3 antagonist tropisetron 27 was found to bind with nanomolar potency to the 7 nicotinic acetylcholine receptor (nAChR) by Macor et al. and the COX-2 inhibitor celecoxib 28 was recently reported to potently inhibit carbonic anhydrases hCA

14、 II and IX but not hCA I,Imatinib 29 for the treatment of chronic myelogenous leukemia (CML) first validated the use of kinase inhibitors, derived from a nonselective inhibitor 30 with activity at PDGF, PKCR, and Src. During subsequent optimization, the PKCR and Src activities were “designed out” vi

15、a the introduction of a “flag methyl” group on the phenylaminopyrimidine scaffold 31.,The “designing out” strategy,Main Areas of Focus in DML Discovery (1990-2004),Figure 4. DML examples published in the primary medicinal chemistry literature between 1990 and 2004, classified according to the main a

16、reas of focus.,5HT Transporter-Based DMLs for Depression,There has been a long-standing hypothesis that depression is associated with reduced levels of 5-HT in the brain.,SERT inhibition has been combined with activity at a secondary monoamine target such as the GPCRs, 5HT1A, 5HT1D, 2, and NK1 recep

17、tors, or the transporters, NET and DAT.,Perez et al.: SERT motifs were attached to the 3-aryloxy-2-propanol framework of pindolol via a common nitrogen to give areasonably well balanced DML 35.,Timms and Torrado et al: 42 suffered from a lack of balance of the two activities as well as cross-reactiv

18、ity at 1 and D2 receptors.,Histamine H1 Receptor-Based DMLs for Allergies,Histamine is a primary mediator of the immediate allergic response in humans. H1 receptor antagonists have found utility in the treatment of hay fever and other allergic reactions but have been largely ineffective for the trea

19、tment of asthma. Interestingly, almost all the H1 antagonists that show some efficacy against asthma are reported to possess additional activities, suggesting that other chemical mediators are also involved in its pathogenesis. As a result, various groups aimed to produce DMLs combining H1 antagonis

20、m with platelet activating factor receptor (PAF), thromboxane- A2 receptor (TxA2R), leukotriene D4 (LTD4), or 5-LOX activity.,Since leukotriene biosynthesis is mediated via 5-LOX, an alternative approach was to combine H1 antagonism with 5-LOX inhibition. The starting points for framework combinatio

21、n were the selective H1 antagonist 64 and the 5-LOX inhibitor 65 (Figure 22). Once again, the strategy took advantage of the flat SAR around the basic nitrogen of the antihistamine to introduce a butynylhydroxyurea group required for 5-LOX inhibition, 66.,Aslanian et al. aimed for a dual H1/H3 antagonist for the treatment of allergic diseases such as nasal congestion. 65 The approach was based on the combination of structural features from the H1 antagonist 70 and the alkylamine class of H3 ant