Aryltriflates as a Neglected Moiety in Medicinal Chemistry: A Case Study from a Lead Optimization of CXCL8 Inhibitors

Abstract

C XCL8 and CXCL1 belong to the class of chemokines or "chemotactic cytokines", a group of low molecular weight 8À14 kDa proteins that regulate the trafficking of leukocytes in the inflamed tissues and other biological processes, including cell growth, angiogenesis, and hematopoiesis. 1À3 CXCL8 binds CXCR1 and CXCR2, whereas CXCL1 is a selective agonist for CXCR2. Both receptors belong to the seven transmembrane G-protein-coupled receptors (GPCRs) superfamily, sharing 78% amino acid identity. 4 The CXCL8 receptor activation has been implicated as a key event in severe chronic diseases, including rheumatoid arthritis, chronic obstructive pulmonary disease, Alzheimer's disease, melanoma, and psoriasis. 5À9 To date, a limited number of small molecular weight CXCL8 inhibitors have been disclosed in the literature. 10,11 Reparixin (1), a potent inhibitor of CXCR1, stemmed from our internal medicinal chemistry programs, was selected as candidate drug after demonstration of its efficacy in several ischemia/reperfusion experimental models. 12 However, its short half-life in humans and the weak activity to CXCR2 limited the exploitation of its potential use for the treatment of chronic conditions. In an earlier paper, SAR results of potent CXCR1/CXCR2 noncompetitive inhibitors were disclosed. 13 As the main outcome of the work, aryltriflates showed a long plasma half-life in the tested species and dual activity to CXCR1 and CXCR2. Aryltriflates are excellent substrates for Stille and Suzuki cross-coupling reactions, Heck reactions, and BuchwaldÀHartwig reactions and are used as intermediates in medicinal chemistry

QSAR Modeling and Data Mining Link Torsades de Pointes Risk to the Interplay of Extent of Metabolism, Active Transport, and hERG Liability

“…The three best models and the resulting consensus model were used to predict the 26 Dompé compounds (Tables and , Figure ) . These molecules were taken from different drug discovery projects targeting both ion channels and G-protein coupled receptors. − Intriguingly, not only this data set was predicted with an accuracy of up to 0.88 (PLSD-VS+ model), but the predicted scores of the three model were also well correlated with the experimental activity ( r 2 > 0.60) (Figure ).…”

“…The synthesis of compounds 1 – 13 is reported elsewhere. − Compounds 14 – 22 were synthesized as described in the Supporting Information. Compound 23 was purchased from Erregierre, 24 – 28 and 30 were purchased from Sigma-Aldrich, 29 was purchased from APIchem, and 31 was purchased from Tocris Bioscience .…”

“…At Dompé laboratories, the putative hERG interaction of structurally diverse compounds is routinely evaluated in the early phase of the drug discovery process, in order to timely detect hERG liability. This set is in part composed of molecules ( 1 – 13 , 23 – 26 ) already published, and in part ( 14 – 22 ) composed of molecules whose synthesis is first described here; for all of them the hERG inhibition activity is reported here for the first time. − Five other molecules ( 27 – 31 ) are included since they are reported as internal reference standards. The activity is expressed as percentage of radiolabeled astemizole bound after incubation with a fixed concentration of 10 μM test compound .…”

C–H Triflation of BINOL Derivatives Using DIH and TfOH

“…As the trifluoromethane­sulfonate (triflate, TfO−) group is a good leaving group, aryl triflates have been recognized as practical coupling precursors in transition metal-catalyzed cross-coupling reactions . Also, since the trifluoromethyl group increases the lipophilicity of compounds, in addition to its synthetic utilities, the introduction of a triflate group is valuable for exploring new types of bioactive compounds . Classically, aryl triflates can be easily synthesized from phenol derivatives using trifluoromethanesulfonylation reagents such as trifluoromethane­sulfonic anhydride (Tf 2 O) and bis­(trifluoromethane­sulfonyl)­imide salts.…”

Oxidative para-Triflation of Acetanilides

“…Moreover, aryltriflates bearing a trimethylsilyl group at the ortho position are the most convenient aryne precursors . Also, a recent study has shown that the aryltriflate moiety has the ability to improve the biological activity of some medicinal compounds …”