Discovery of a Novel Series of N-Phenylindoline-5-sulfonamide Derivatives as Potent, Selective, and Orally Bioavailable Acyl CoA:Monoacylglycerol Acyltransferase-2 Inhibitors

Abstract

Acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has attracted interest as a novel target for the treatment of obesity and metabolic diseases. Starting from N-phenylbenzenesulfonamide derivative 1 with moderate potency for MGAT2 inhibition, we explored an effective location of the hydrophobic group at the 1-position to enhance MGAT2 inhibitory activity. Shifting the hydrophobic group to the adjacent position followed by introduction of a bicyclic central core to restrict the substituent orientation produced N-phenylindoline-5-sulfonamide derivative 10b, which displayed much improved potency, with an IC50 value of 1.0 nM. This compound also exhibited excellent selectivity (greater than 30,000-fold) against related acyltransferases (MGAT3, DGAT1, DGAT2, and ACAT1). Subsequent optimization efforts were directed toward improving pharmacokinetic profiles, which resulted in the identification of 5-[(2,4-difluorophenyl)sulfamoyl]-7-(2-oxopyrrolidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indole-1-carboxamide (24d) endowed with potent MGAT2 inhibitory activity (IC50 = 3.4 nM) and high oral bioavailability (F = 52%, mouse). In a mouse oral fat tolerance test, oral administration of this compound effectively suppressed the elevation of plasma triacylglycerol levels.

Optimization of a novel series of N-phenylindoline-5-sulfonamide-based acyl CoA:monoacylglycerol acyltransferase-2 inhibitors: Mitigation of CYP3A4 time-dependent inhibition and phototoxic liabilities

“…To further widen the HOMO-LUMO gap, we designed compounds with an electron-rich 5-membered heterocycle at the 5-position on the pyrimidine ring while maintaining a terminal trifluoromethyl group that could effectively interact with the presumed hydrophobic site of MGAT2. 13 As expected, compared with 27a, the pyrazole derivatives 27d and 27e exhibited larger HOMO-LUMO gaps and greatly improved phototoxic liability (Table 3) This approach was found to be effective in the biaryl series, and the consequent compound 34 exhibited improved potency and reduced lipophilicity, resulting in a higher LLE value. In addition, no phototoxicity was observed for this compound.…”

“…As described in a previous report, 13 the sulfonyl chloride 3 smoothly reacted with 2,4-difluoroaniline or p-anisidine in N,N-dimethylacetamide without the addition of a base to give the corresponding sulfonamide in good yields. However, the reaction of 3 with 4-chloro-2,6-difluoroaniline resulted in a poor yield (10-20% yield) under the same condition, probably because of the low basicity and nucleophilicity of the aniline.…”

“…We applied a strategy to rigidify the substituent at the indoline 1-position to restrict conformation of the terminal hydrophobic motif, which is important for interaction with MGAT2. 13 Thereby, several biaryl-type substituents at the 1-position were designed by the conversion of the urea linkage of 9a to an aryl ring ( Figure 4). Despite their attractive potencies for MGAT2 inhibition, it was found that the biaryl compounds 23 and 27a exhibited cytotoxicity against BALB/c 3T3 cells under UV irradiation condition, whereas cytotoxic effect was not observed under a condition without UV exposure (Table 3), thereby indicating potential phototoxic liability.…”

“…We previously reported the discovery of a novel series of N-phenylindoline-5-sulfonamide derivatives as potent, selective, and orally bioavailable MGAT2 inhibitors, as exemplified by 2 (Figure 1). 13 Compound 2 exhibited potent MGAT2 inhibitory activity and suppressed the elevation of TG in a mouse oral fat tolerance test (OFTT) after oral administration. These attractive profiles motivated us to evaluate this compound in detail in terms of drug-drug interactions (DDIs) and toxicity profiles.…”

Identification of 2-[2-(4-<i>tert</i>-Butylphenyl)ethyl]-<i>N</i>-[4-(3-cyclopentylpropyl)-2-fluorophenyl]-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide as an Orally Active MGAT2 Inhibitor

“…1, AstraZeneca's compound 1 reported in the literature showed potent MGAT2 inhibitory activity and a significant reduction of plasma TG concentration after an oral administration at a dose of 150 mg/kg in mice oral lipid tolerance test. [16][17][18] We have also reported an orally available MGAT2 inhibitor, 19) 2-[2-(4-tert-butylphenyl)-ethyl]-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide 2, which demonstrated the significant suppression of fat absorption in mice oral lipid tolerance test at an oral dose of 100 mg/kg.The identification of compound 2 promoted us to explore a more potent and orally available MGAT2 inhibitor, and our efforts have been focused on optimization of compound 2. As…”