کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1368505 | 981701 | 2016 | 7 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Synthesis and evaluation of a series of 4-azaindole-containing p21-activated kinase-1 inhibitors Synthesis and evaluation of a series of 4-azaindole-containing p21-activated kinase-1 inhibitors](/preview/png/1368505.png)
A series of 4-azaindole-containing p21-activated kinase-1 (PAK1) inhibitors was prepared with the goal of improving physicochemical properties relative to an indole starting point. Indole 1 represented an attractive, non-basic scaffold with good PAK1 affinity and cellular potency but was compromised by high lipophilicity (c log D = 4.4). Azaindole 5 was designed as an indole surrogate with the goal of lowering log D and resulted in equipotent PAK1 inhibition with a 2-fold improvement in cellular potency over 1. Structure–activity relationship studies around 5 identified additional 4-azaindole analogs with superior PAK1 biochemical activity (Ki <10 nM) and up to 24-fold selectivity for group I over group II PAKs. Compounds from this series showed enhanced permeability, improved aqueous solubility, and lower plasma protein binding over indole 1. The improvement in physicochemical properties translated to a 20-fold decrease in unbound clearance in mouse PK studies for azaindole 5 relative to indole 1.
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Journal: Bioorganic & Medicinal Chemistry Letters - Volume 26, Issue 15, 1 August 2016, Pages 3518–3524