In This Issue pubs.acs.org/acsmedchemlett
■
NOVEL POTENT AND SELECTIVE TRICYCLIC BRUTON’S TYROSINE KINASE INHIBITORS Bruton’s tyrosine kinase (Btk) is central to the function of B cells and myeloid cells and thus presents a therapeutic target for immunological disorders and B-cell lymphomas. Development of Btk inhibitors is actively ongoing within the pharmaceutical community, and one compound, ibrutinib, was recently approved for the treatment of certain types of cancers. However, approved Btk inhibitors for nononcology applications are lacking. In this issue’s Featured Letter, Wang et al. (DOI: 10.1021/ acsmedchemlett.7b00103) detail their work revolving around the development of novel Btk inhibitors. Their initial efforts surveyed tricyclic and bicyclic derivatives of an uncyclized precursor from which various potent Btk compounds were identified. Subsequent optimization focused on designing molecules with improved solubility profiles. After drug metabolism and pharmacokinetic studies, the potent and selective lead compound G-744 was identified that exhibited efficacy in a rat collagen induced arthritis model comparable to that of the anti-inflammatory dexamethasone. Current work by the authors is focusing on developing this lead molecule into a clinical candidate.
Mahasenan et al. (DOI: 10.1021/acsmedchemlett.7b00130) report herein the design, synthesis, and biological characterization of selective MMP-13 inhibitors. An initial molecular dynamics simulation of three MMPs revealed differences within a cavity near the active site. The authors subsequently developed and evaluated a virtual library of nearly 30,000 benzooxazinones, from which 19 compounds were chosen for further assessment. Following their synthesis and in vitro studies with a panel of MMPs, selective inhibitors for MMP-13 were identified. Final in vivo studies with the most potent inhibitor demonstrated favorable pharmacokinetic properties. The benzooxazinone compounds described could potentially be applied to further probe the various functions of MMPs.
■
DEVELOPMENT OF CANNABINOID RECEPTOR TYPE 2 AGONISTS Cannabinoid receptor 2 (CB2) is a G protein-coupled receptor that could potentially serve as a therapeutic target to address pain and immune-related diseases. While several CB2 ligands have been identified, none have reached the market, possibly due to poor pharmacokinetic properties. Herein, Qian et al. (DOI: 10.1021/acsmedchemlett.7b00007) describe in their Note the optimization of their previously developed quinolone-2,4(1H,3H)-dione lead compound that proved to be a potent CB2 agonist. The efforts in the current study aimed to improve some of the properties of this class of molecules, such as their lipophilicity and separation of isomers. The authors developed two series of compounds,
■
USING CONFORMATIONAL DYNAMICS TO GUIDE SELECTIVE INHIBITOR DEVELOPMENT OF RELATED MATRIX METALLOPROTEINASES Matrix metalloproteinases (MMPs) are a group of proteins that are involved in numerous physiological functions. This requires strict regulation of their enzymatic activities as disruption of this regulation can lead to various pathologies, such as cancer and arthritis. Substantial structural similarities between MMP active sites complicate development efforts for selective inhibitors. © 2017 American Chemical Society
Published: June 8, 2017 587
DOI: 10.1021/acsmedchemlett.7b00218 ACS Med. Chem. Lett. 2017, 8, 587−588
ACS Medicinal Chemistry Letters
In This Issue
quinazoline-2,4(1H,3H)-diones and pyrimidine-2,4(1H,3H)diones, and performed detailed SAR studies. This led to the discovery of potent and selective CB2 agonists with improved lipophilicity profiles that provide an avenue for further optimization efforts.
588
DOI: 10.1021/acsmedchemlett.7b00218 ACS Med. Chem. Lett. 2017, 8, 587−588
