Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States.
J Med Chem. 2020 Sep 10;63(17):9742-9751. doi: 10.1021/acs.jmedchem.0c00868. Epub 2020 Aug 20.
The blood-brain barrier is a major impediment for targeted central nervous system (CNS) therapeutics, especially with carboxylic acid-containing drugs. Nuclear receptor modulators, which often feature carboxylic acid motifs for target engagement, have emerged as a class of potentially powerful therapeutics for neurodegenerative CNS diseases. Herein is described a prodrug strategy that directs the biodistribution of parent drug nuclear receptor modulators into the CNS while masking them as functional receptor ligands in the periphery. This prodrug strategy targets a specific amidase, fatty acid amide hydrolase (FAAH), an enzyme with enriched expression in the CNS. Our results demonstrate that this prodrug strategy can be generalized to a variety of carboxylic acid-containing drug structures that satisfy the structural requirements of blood-brain barrier diffusion and FAAH substrate recognition.
血脑屏障是靶向中枢神经系统 (CNS) 治疗的主要障碍，尤其是对于含有羧酸的药物。核受体调节剂通常具有用于靶标结合的羧酸基序，已成为一类用于神经退行性 CNS 疾病的潜在有效治疗药物。本文描述了一种前药策略，该策略可将母体药物核受体调节剂的分布引导至中枢神经系统，同时在外周将其掩蔽为功能性受体配体。这种前药策略针对一种特定的酰胺酶，即脂肪酸酰胺水解酶 (FAAH)，这是一种在中枢神经系统中表达丰富的酶。我们的研究结果表明，这种前药策略可以推广到满足血脑屏障扩散和 FAAH 底物识别结构要求的各种含有羧酸的药物结构。
