Identification of a Series of N-Methylpyridine-2-carboxamides as Potent and Selective Inhibitors of the Second Bromodomain (BD2) of the Bromo and Extra Terminal Domain (BET) Proteins

Abstract

Domain-specific BET bromodomain ligands represent an attractive target for drug discovery with the potential to unlock the therapeutic benefits of antagonizing these proteins without eliciting the toxicological aspects seen with pan-BET inhibitors. While we have reported several distinct classes of BD2 selective compounds, namely, GSK620, GSK549, and GSK046, only GSK046 shows high aqueous solubility. Herein, we describe the lead optimization of a further class of highly soluble compounds based upon a picolinamide chemotype. Focusing on achieving >1000-fold selectivity for BD2 over BD1 ,while retaining favorable physical chemical properties, compound 36 was identified as being 2000-fold selective for BD2 over BD1 (Brd4 data) with >1 mg/mL solubility in FaSSIF media. 36 represents a valuable new in vivo ready molecule for the exploration of the BD2 phenotype.

Fragment-based Scaffold Hopping: Identification of Potent, Selective, and Highly Soluble Bromo and Extra Terminal Domain (BET) Second Bromodomain (BD2) Inhibitors

“…Contrastingly, a sixmembered pyridine series was able to obtain potency increases in this region. 19 It was believed pyrazole (S)-10 should also be able to access the ZA channel based on this hypothesis. Pleasingly (S)-10 did indeed show a significant potency increase relative to 9 and especially pyridone (S)-7.…”

“…It is believed the reason for this is the presence of the pyridone carbonyl group, which would likely sterically clash with the methyl group of ( S )-7 in its required bioactive conformation. Contrastingly, a six-membered pyridine series was able to obtain potency increases in this region . It was believed pyrazole ( S )-10 should also be able to access the ZA channel based on this hypothesis.…”

“…(S)-N 4 -(2-Hydroxyethyl)-N 2 -methyl-5-(1-phenylethyl)furan-2,4dicarboxamide (19). A solution of (S)-5-(methylcarbamoyl)-2-(1phenylethyl)furan-3-carboxylic acid (40 mg, 0.15 mmol) and HATU (66.8 mg, 0.176 mmol) in DMF (0.9 mL) at room temperature was treated with DIPEA (0.077 mL, 0.44 mmol) and, after 5 min, with 2aminoethan-1-ol (10.6 μL, 0.176 mmol).…”

Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors

“…For the latter, the starting point was pyridyl amide 4 (Table 1), whose amide AcK mimetic is reversed in direction compared to that of 3. 63 Compound 4 was an early secondgeneration lead originating from the selective probes that have been previously introduced (e.g., 5, GSK620, 64 Table 1), showing reasonable potency and selectivity for BD2 alongside acceptable physicochemical properties with a chromLogD of 3.7 and high solubility and permeability.…”

CRCM5484: A BET- BDII Selective Compound With Differential Anti-Leukemic Drug Modulation

“…Despite a high homology across the BDs in the BET family, several selective inhibitors of the BDI or BDII BET domains have recently emerged in the literature [24][25][26][27] , but few are currently engaged in clinical trials. The first developed selective compounds were BDI selective, the most extensively studied are olinone 28 , MS402 29 , and GSK778 30 .…”