Division of Biomedical Sciences, St George's, University of London, UK.
Future Med Chem. 2013 Feb;5(2):147-61. doi: 10.4155/fmc.12.204.
Existing therapies for allergic asthma are far from perfect: the global prevalence of disease increases despite them and they are poorly effective in dealing with the exacerbations that account for hospitalization and asthma deaths. Commercially, there are pressures on these existing medicines too--a growing threat from generics and reluctance by payers to reimburse for increasingly marginal improvements in medicines with precedented mechanisms. Experience shows that attempts to devise selective small-molecule interventions directed at the myriad of downstream effector pathways has not been a fertile ground for the development of effective new medicines. An alternative strategy, exploiting breakthroughs in understanding the molecular basis of allergenicity and the key role of innate immune mechanisms in asthma, is to direct new approaches to the disease triggers themselves: allergens. This raises interesting possibilities for anti-Lipinski drug design (extracellular nonhuman targets, inhaled delivery) and creates unprecedented pharmacological opportunities in the therapeutic area.
尽管有这些治疗方法,但全球疾病患病率仍在上升,而且它们在应对导致住院和哮喘死亡的恶化方面效果不佳。从商业角度来看,这些现有药物也面临压力——仿制药的威胁越来越大,支付方不愿意为药物机制已有先例的、收益逐渐减少的改进提供报销。经验表明,试图设计针对众多下游效应途径的选择性小分子干预措施,并不是开发有效新药的肥沃土壤。另一种策略是利用对过敏原性的分子基础和先天免疫机制在哮喘中的关键作用的突破性认识,将新方法直接应用于疾病触发因素本身:过敏原。这为反 Lipinski 药物设计(细胞外非人类靶标,吸入式给药)带来了有趣的可能性,并在治疗领域创造了前所未有的药理学机会。