Boron-Based Inhibitors of the NLRP3 Inflammasome

Abstract

SummaryNLRP3 is a receptor important for host responses to infection, yet is also known to contribute to devastating diseases such as Alzheimer's disease, diabetes, atherosclerosis, and others, making inhibitors for NLRP3 sought after. One of the inhibitors currently in use is 2-aminoethoxy diphenylborinate (2APB). Unfortunately, in addition to inhibiting NLRP3, 2APB also displays non-selective effects on cellular Ca2+ homeostasis. Here, we use 2APB as a chemical scaffold to build a series of inhibitors, the NBC series, which inhibit the NLRP3 inflammasome in vitro and in vivo without affecting Ca2+ homeostasis. The core chemical insight of this work is that the oxazaborine ring is a critical feature of the NBC series, and the main biological insight the use of NBC inhibitors led to was that NLRP3 inflammasome activation was independent of Ca2+. The NBC compounds represent useful tools to dissect NLRP3 function, and may lead to oxazaborine ring-containing therapeutics.

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

“…Brain penetrability and efficacy in attenuating neuroinflammation was confirmed when mice administered MCC950 24 h post traumatic brain injury had significant improvements in neurological function as well as decreased IL-1β and caspase 3 mediated apoptosis (Ismael et al, 2018). Another molecular entity under preclinical development targeting the NLRP3 inflammasome leverages oxaborine moieties (Baldwin et al, 2017). However, in preclinical studies when compared to MCC950, the oxaborine compound failed to elicit the same dose-dependent reduction of IL-1β in NLRP3 −/− mice administered LPS.…”

Design, Synthesis and Evaluation of Oxazaborine Inhibitors of the NLRP3 Inflammasome

“…We recently published the NBC series of NLRP3 inflammasome inhibitors reporting that key features required for bioactivity were the oxazaborine ring and CCl 3 group . Here we have further refined the SAR and shown that substitutions on the aryl rings do not enhance inhibitory activity, and that the lipophilicity of the CCl 3 group is key to inhibitory activity.…”

“…General : ( Z )‐4‐Amino‐5,5,5‐trichloropent‐3‐en‐2‐one and ( Z )‐2‐acetyl‐3‐amino‐4,4,4‐trichlorobut‐2‐enamide intermediates were prepared as previously described . All other chemicals, solvents and deuterated solvents were purchased from Sigma–Aldrich, Alfa‐Aesar or Fisher Scientific.…”

“…We recently reported on the discovery of new boron‐based small molecules as potent NLRP3 inhibitors . Three of the oxazaborine compounds screened, BC7 ( 1 ), BC23 ( 2 ) and NBC6 ( 3 , Figure ) were particularly effective inhibitors of IL‐1β release.…”

“…[24,25] Nevertheless, there is still an eed for new NLRP3 inhibitors as there are currently no approved small molecule inhibitors of the NLRP3i nflammasome available clinically.We recently reported on the discovery of new boron-based small molecules as potent NLRP3 inhibitors. [26] Three of the oxazaborinec ompounds screened, BC7( 1), BC23 (2)a nd NBC6 (3,F igure1) were particularly effective inhibitors of IL-1b release. The pharmacophore for these molecules responsible for NLRP3 inhibition is the oxazaboriner ing and the highly electron-withdrawing trichloromethyl (CCl 3 )g roup.…”