Optimization of the efflux ratio and permeability of covalent irreversible BTK inhibitors. Issue 20 (1st November 2018)

• Record Type: Journal Article
• Authors: Qiu, Hui; Liu-Bujalski, Lesley; Caldwell, Richard D.; Viacava Follis, Ariele; Gardberg, Anna; Goutopoulos, Andreas; Grenningloh, Roland; Head, Jared; Johnson, Theresa; Jones, Christopher C.V.; Jones, Reinaldo; Mochalkin, Igor; Morandi, Federica; Neagu, Constantin; Potnick, Justin; Sherer, Brian
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 20(2018)
• Page Start: 3307
• Page End: 3311
• Publication Date: 2018-11-01
• Subjects: Btk inhibitor -- Efflux ratio -- tPSA -- cLogP -- Steric hindrance; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.09.018
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: A novel series of covalent Btk inhibitors was discovered. Hit molecules showed high ER. Optimization of ER led to the discovery of the lead molecule. Abstract: Bruton's tyrosine kinase (Btk) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage (e.g. B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible Btk inhibitors targeting Cys481 within the ATP-binding pocket have been applied in the treatment of B-cell malignancies. Starting from a fragment, we discovered a novel series of potent covalent irreversible Btk inhibitors that bear N -linked groups occupying the solvent accessible pocket (SAP) of the active site of the Btk kinase domain. The hit molecules, however, displayed high P-gp mediated efflux ratio (ER) and poor A-B permeability in Caco-2 assay. By decreasing tPSA, installing steric hindrance and adjusting clogP, one top molecule9 was discovered, which showed a 99% decrease in efflux ratio and a 90-fold increase in A-B permeability compared to hit molecule1 .