DrugDiscovery-DML药物发现.ppt

* * 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 future, 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-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 risk-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 regarded 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) 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 “Designing In” Approaches Conjugates The covalent linking of selective adenosine A1 and A3 agonists by Jacobson et al. using a rigid ethynyl-based s