Design, Synthesis, and Biological Evaluation of N,N-Disubstituted-4-arylthiazole-2-methylamine Derivatives as Cholesteryl Ester Transfer Inhibitors

Cholesteryl ester transfer protein (CETP) has been identified as a potential target for cardiovascular disease (CVD) for its important role in the reverse cholesteryl transfer (RCT) process. In our previous work, compound 5 was discovered as a moderate CETP inhibitor. The replacement of the amide linker by heterocyclic aromatics and then a series of N,N-substituted-4-arylthiazole-2-methylamine derivatives were designed by utilizing a conformational restriction strategy. Thirty-six compounds were synthesized and evaluated for their CETP inhibitory activities. Structure-activity relationship studies indicate that electron donor groups substituted ring A, and electron-withdrawing groups at the 4-position of ring B were critical for potency. Among these compounds, compound 30 exhibited excellent CETP inhibitory activity (IC50 = 0.79 ± 0.02 μM) in vitro and showed an acceptable metabolic stability.


Introduction
Robust evidence suggests that a high level of low-density lipoprotein cholesterol (LDL-C) and a low level of high-density lipoprotein cholesterol (HDL-C) are closely associated with cardiovascular disease (CVD) [1][2][3][4]. Epidemiological studies have identified that each 1 mmol/L decrease of LDL-C reduces cardiovascular events by 22% [5]. In contrast to LDL-C, the risk of cardiovascular events will be reduced 2% to 3% for each 0.1 mg/dL increase in HDL-C [6]. Despite the successful utilization of statins in clinical treatment for reducing LDL-C levels, the residual risk of CVD events remains at high levels [7][8][9][10]. Plasma cholesteryl ester transfer protein (CETP), secreted mainly from the liver, plays a coordinating part in reverse cholesteryl transfer (RCT) that facilitates the transfer of triglyceride and cholesteryl ester (CE) between lipoproteins. The elevation of HDL-C via inhibiting CETP is an effective strategy for reducing the risk of cardiovascular events.
Up to now, several CETP inhibitors have been reported, and four of them have exhibited preeminent activity in phase III clinical trials ( Figure 1) [11]. Torcetrapib was the first small molecule CETP inhibitor be appraised in the clinic. Early evidence has demonstrated that torcetrapib exhibited a dose-dependent increase of HDL-C greater than 100% and resulted in incremental LDL-C decreasing by up to 42% in human studies. However, torcetrapib was prematurely halted because of off-target hyperaldosteronism that lead to a 58% increase in deaths in the torcetrapib/atorvastatin group In previous work, we found that compound 5 exhibited weak CETP inhibition activity. Based on the structure-activity relationship of compound 5, we replaced amide fragments with different heterocyclic aromatics and benzoheteroaromatics to decrease molecular flexibility while keeping the key pharmacophores invariant. As shown in Figure 2, the replacement of amide linker with seven fragments revealed a slight increase in activity, and the replacement of compound 17d with a 4-phenylthiazole side chain showed better CETP inhibition activities (IC50 = 9.03 ± 0.21 μM). Under the consideration of the structural novelty and the difficulty of synthesis, compound 17d was selected as the leader for structure optimization, and a series of N,N-substituted-4-arylthiazole-2-methylamine derivatives were synthesized. Further optimization efforts in part A and part B led to the discovery of compound 30 (IC50 = 0.79 ± 0.02 μM).  In previous work, we found that compound 5 exhibited weak CETP inhibition activity. Based on the structure-activity relationship of compound 5, we replaced amide fragments with different heterocyclic aromatics and benzoheteroaromatics to decrease molecular flexibility while keeping the key pharmacophores invariant. As shown in Figure 2, the replacement of amide linker with seven fragments revealed a slight increase in activity, and the replacement of compound 17d with a 4-phenylthiazole side chain showed better CETP inhibition activities (IC 50 = 9.03 ± 0.21 µM). Under the consideration of the structural novelty and the difficulty of synthesis, compound 17d was selected as the leader for structure optimization, and a series of N,N-substituted-4-arylthiazole-2-methylamine derivatives were synthesized. Further optimization efforts in part A and part B led to the discovery of compound 30 (IC 50 = 0.79 ± 0.02 µM). CETP inhibition and no off-target effects. However, the phase III clinical trial was terminated due to the fact that dalcetrapib did not significantly decrease the risk of cardiovascular events [15,16].
Recently, DalCor Pharmaceuticals licensed dalcetrapib from Roche to conduct clinical trials for the treatment of acute coronary syndrome. The effect of evacetrapib on a reduction in CVD events was similar to trocetrapib, while avoiding torcetrapib's side effects [17]. Subsequently, the ACCELERATE trials of evacetrapib were terminated after just over two years, but the reason for failure has not been announced by Lilly. Anacetrapib is currently ongoing in phase III trials at Merck and Co. (Kenilworth, NJ, USA) for the treatment of coronary artery disease. More recently, Merck announced that anacetrapib significantly reduced the incidence of major coronary events, while anacetrapib's safety profile was generally consistent with that of previous studies of the drug. The phase II clinical trials demonstrated that AMG-899 seems to be free of the off-target effects of torcetrapib, effectively reduced LDL-C levels by 45.3%, and increased HDL-C levels by 179.1% [18]. In previous work, we found that compound 5 exhibited weak CETP inhibition activity. Based on the structure-activity relationship of compound 5, we replaced amide fragments with different heterocyclic aromatics and benzoheteroaromatics to decrease molecular flexibility while keeping the key pharmacophores invariant. As shown in Figure 2, the replacement of amide linker with seven fragments revealed a slight increase in activity, and the replacement of compound 17d with a 4-phenylthiazole side chain showed better CETP inhibition activities (IC50 = 9.03 ± 0.21 μM). Under the consideration of the structural novelty and the difficulty of synthesis, compound 17d was selected as the leader for structure optimization, and a series of N,N-substituted-4-arylthiazole-2-methylamine derivatives were synthesized. Further optimization efforts in part A and part B led to the discovery of compound 30 (IC50 = 0.79 ± 0.02 μM).

In Vitro Activity and Structure-Activity Relationships
The biological activity of N,N-disubstituted-aryl-methylamine derivatives and reference compound anacetrapib (4) against CETP was evaluated by a BODIPY-CE fluorescence assay with the CETP RP Activity Assay Kit (catalog # RB-RPAK; Roar, New York, NY, USA). The results (Tables S1 and S2 in Supporting Information) showed that most of the target compounds exhibit potent CETP inhibitory activity.
As shown in Table 1, 4-phenylthiazole (17d) revealed better activity than other links. Further optimization based on N,N-substituted-4-arylthiazole-2-methylamine scaffolding was underway, and in vitro activity against CETP is shown in Table 2. We investigated the relationship between various groups at the 2-position, 3-position, and 4-position of the benzene (Ring A) and the CETP inhibitory activity. The introduction of the 3,4-dimethoxy group (22, 30-33) was beneficial to activity. The replacement of hydrogen by trifluoromethoxy (23) and N-methyl-5-yl-pyrazole (29) at the 3-position was detrimental to activity. Changing the 3-H group to 3-OCH3 (21) and 3-CF3 (24) slightly decreased CETP inhibition activity. Thus, we could conclude that electron donor groups, in particular the 3,4-dimethoxy group, substituted in ring A were conducive to activity. Next, the effect of the aromatic ring on activity was investigated; then phenyl, 2-thienyl and N-methyl-5-yl-pyrazolyl were induced to modify ring A. Specifically, it was observed that the activity of compound 27 (IC50 = 1.02 ± 0.01 μM) was a seven-fold improvement over compound 26 (IC50 = 8.98 ± 0.05 μM) and an eight-fold improvement over compound 25 (IC50 = 9.05 ± 0.08 μM). Compared to the phenyl-substituted ring A at the 3-position (26), 2-thienyl (28) and N-methyl-5-yl-pyrazolyl (29) showed no advantage. The results from the modification of the ring A moiety indicated that phenyl-substituted compounds were favorable for activity compared to thienyl and pyrazolyl, and the position of the phenyl group provided an important contribution to the inhibitory activity. However, the potency of compound 30 (IC50 = 0.79 ± 0.02 μM) was superior to compound 27, and, for that reason, the (3,4-dimethoxyl) phenyl fragment was chosen for further study of the relationship between ring B and the CETP inhibitory activity. For this purpose, another nineteen compounds, 31 to 49, were synthesized and evaluated for their activities. Compounds containing electron withdrawing groups (31 to 33) at the 4-position of ring B revealed significant improvement of activity compared to those compounds with electron donor groups (42 to 45). The nitro group at the 4-position of ring B (30) exhibited better potency of CETP inhibitory activity than that substituted at the 2-position (35) and the 3-position (34). The introduction of bromine (36), 1-methylpyrazole (37, 39), isoxazole (38), thiazole (40), and benzene (41) was tolerated, but 4-morpholinyl (49) led to a disappearance of activity. Replacing the nitro group on the 4-position of ring B with an ester side chain (48) caused nearly a 10-fold decrease of activity. Changing the 4-NH2 group (44) to a 4-NHCOCH3 group (46) showed a dramatic decrease in the activity; however, potency was recovered when modified by a 4-NHCOCF3 group (45) was introduced. Based on these in vitro structure-activity relationshipstudies, we could speculate that

In Vitro Activity and Structure-Activity Relationships
The biological activity of N,N-disubstituted-aryl-methylamine derivatives and reference compound anacetrapib (4) against CETP was evaluated by a BODIPY-CE fluorescence assay with the CETP RP Activity Assay Kit (catalog # RB-RPAK; Roar, New York, NY, USA). The results showed that most of the target compounds exhibit potent CETP inhibitory activity.
As shown in Table 1, 4-phenylthiazole (17d) revealed better activity than other links. Further optimization based on N,N-substituted-4-arylthiazole-2-methylamine scaffolding was underway, and in vitro activity against CETP is shown in Table 2. We investigated the relationship between various groups at the 2-position, 3-position, and 4-position of the benzene (Ring A) and the CETP inhibitory activity. The introduction of the 3,4-dimethoxy group (22, 30-33) was beneficial to activity. The replacement of hydrogen by trifluoromethoxy (23) and N-methyl-5-yl-pyrazole (29) at the 3-position was detrimental to activity. Changing the 3-H group to 3-OCH 3 (21) and 3-CF 3 (24) slightly decreased CETP inhibition activity. Thus, we could conclude that electron donor groups, in particular the 3,4-dimethoxy group, substituted in ring A were conducive to activity. Next, the effect of the aromatic ring on activity was investigated; then phenyl, 2-thienyl and N-methyl-5-yl-pyrazolyl were induced to modify ring A. Specifically, it was observed that the activity of compound 27 (IC 50 = 1.02 ± 0.01 µM) was a seven-fold improvement over compound 26 (IC 50 = 8.98 ± 0.05 µM) and an eight-fold improvement over compound 25 (IC 50 = 9.05 ± 0.08 µM). Compared to the phenyl-substituted ring A at the 3-position (26), 2-thienyl (28) and N-methyl-5-yl-pyrazolyl (29) showed no advantage. The results from the modification of the ring A moiety indicated that phenyl-substituted compounds were favorable for activity compared to thienyl and pyrazolyl, and the position of the phenyl group provided an important contribution to the inhibitory activity. However, the potency of compound 30 (IC 50 = 0.79 ± 0.02 µM) was superior to compound 27, and, for that reason, the (3,4-dimethoxyl) phenyl fragment was chosen for further study of the relationship between ring B and the CETP inhibitory activity. For this purpose, another nineteen compounds, 31 to 49, were synthesized and evaluated for their activities. Compounds containing electron withdrawing groups (31 to 33) at the 4-position of ring B revealed significant improvement of activity compared to those compounds with electron donor groups (42 to 45). The nitro group at the 4-position of ring B (30) exhibited better potency of CETP inhibitory activity than that substituted at the 2-position (35) and the 3-position (34). The introduction of bromine (36), 1-methylpyrazole (37, 39), isoxazole (38), thiazole (40), and benzene (41) was tolerated, but 4-morpholinyl (49) led to a disappearance of activity. Replacing the nitro group on the 4-position of ring B with an ester side chain (48) caused nearly a 10-fold decrease of activity. Changing the 4-NH 2 group (44) to a 4-NHCOCH 3 group (46) showed a dramatic decrease in the activity; however, potency was recovered when modified by a 4-NHCOCF 3 group (45) was introduced. Based on these in vitro structure-activity relationshipstudies, we could speculate that electron-withdrawing groups at the 4-position of ring B provide an important contribution to the potency compared with electron withdrawing groups and bulkier rigid fragments. electron-withdrawing groups at the 4-position of ring B provide an important contribution to the potency compared with electron withdrawing groups and bulkier rigid fragments.  electron-withdrawing groups at the 4-position of ring B provide an important contribution to the potency compared with electron withdrawing groups and bulkier rigid fragments.  electron-withdrawing groups at the 4-position of ring B provide an important contribution to the potency compared with electron withdrawing groups and bulkier rigid fragments.  electron-withdrawing groups at the 4-position of ring B provide an important contribution to the potency compared with electron withdrawing groups and bulkier rigid fragments.  electron-withdrawing groups at the 4-position of ring B provide an important contribution to the potency compared with electron withdrawing groups and bulkier rigid fragments.  electron-withdrawing groups at the 4-position of ring B provide an important contribution to the potency compared with electron withdrawing groups and bulkier rigid fragments.  electron-withdrawing groups at the 4-position of ring B provide an important contribution to the potency compared with electron withdrawing groups and bulkier rigid fragments.  electron-withdrawing groups at the 4-position of ring B provide an important contribution to the potency compared with electron withdrawing groups and bulkier rigid fragments.   electron-withdrawing groups at the 4-position of ring B provide an important contribution to the potency compared with electron withdrawing groups and bulkier rigid fragments.  electron-withdrawing groups at the 4-position of ring B provide an important contribution to the potency compared with electron withdrawing groups and bulkier rigid fragments.  electron-withdrawing groups at the 4-position of ring B provide an important contribution to the potency compared with electron withdrawing groups and bulkier rigid fragments.  electron-withdrawing groups at the 4-position of ring B provide an important contribution to the potency compared with electron withdrawing groups and bulkier rigid fragments.  electron-withdrawing groups at the 4-position of ring B provide an important contribution to the potency compared with electron withdrawing groups and bulkier rigid fragments.  electron-withdrawing groups at the 4-position of ring B provide an important contribution to the potency compared with electron withdrawing groups and bulkier rigid fragments.  electron-withdrawing groups at the 4-position of ring B provide an important contribution to the potency compared with electron withdrawing groups and bulkier rigid fragments.

In Vitro Metabolic Stability Study
Based on the result of the in vitro CETP inhibitory assay, potent inhibitors 30 and 32 were selected for the in vitro metabolic stability study. As shown in Table 3, compound 30 showed weak stability, with a clearance rate of 48.1 and 121.7 μL/min/mg in human and rat liver microsomes, while compound 32 exhibited acceptable stability, with a clearance rate of 29.8 and 79.3 μL/min/mg in human and rat liver microsomes.

Chemicals and Instruments
All chemicals and reagents were obtained from commercial sources and were used without purification. TLC, performed on silica gel plates (Indicator F-254), was used to monitor the reactions. Column chromatography, performed on silica gel (200 to 300 mesh) was utilized to purify the compounds. The melting points (uncorrected) were determined on a Buchi 353 melting-point apparatus. The purities of the target compounds were detected by HPLC, performed on a Waters 1525-2489 (Waters, Milford, MA, USA), with a chromatographic column (Kromasil, C-18, 5 μm, 150 mm × 4.6 mm), at ≥95%. The method conditions were as follows: a mixture of solvents H2O (A) and CH3CN (B) (VA:VB = 5:95) as eluent and a flow rate of 1.0 mL/min. Peaks were detected at λ = 254 nm. NMR spectra were collected on Bruker (Billerica, MA, USA) 400 MHz and 600 MHz instruments, using tetramethylchlorosilane as an internal standard and CDCl3 or DMSO-d6 as solvent. ESI-HRMS spectra were obtained on a Bruker Micromass time of flight mass spectrometer. (7). 2-amino-1-phenylethan-1-one hydrochloride 6 (0.50 g, 2.9 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (13 mL, 8.9 mmol) was added. The mixture was cooled, and 2-chloroacetyl chloride (0.45 g, 4.0 mmol) was added in drops at 0 °C. After 2 h, the solution was recovered to room temperature for 16 h. Then the mixture was poured into water (20 mL) and extracted with dichloromethane (10 mL × 3), and the combined organic layers were washed with water (10 mL × 3) and brine (10 mL × 3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether:ethyl acetate = 4:1) to give 7 (0.39 g, 62.9%) as a white solid.

In Vitro Metabolic Stability Study
Based on the result of the in vitro CETP inhibitory assay, potent inhibitors 30 and 32 were selected for the in vitro metabolic stability study. As shown in Table 3, compound 30 showed weak stability, with a clearance rate of 48.1 and 121.7 μL/min/mg in human and rat liver microsomes, while compound 32 exhibited acceptable stability, with a clearance rate of 29.8 and 79.3 μL/min/mg in human and rat liver microsomes. a Clearance rate, CL < 100 μL/min/mg means acceptable stability; b The abbreviation of no co-factor. No NADPH (nicotinamide adenine dinucleotide phosphate) regenerating system is added into NCF (no co-factor) sample (replaced by buffer) during the 60 minute incubation.

Chemicals and Instruments
All chemicals and reagents were obtained from commercial sources and were used without purification. TLC, performed on silica gel plates (Indicator F-254), was used to monitor the reactions. Column chromatography, performed on silica gel (200 to 300 mesh) was utilized to purify the compounds. The melting points (uncorrected) were determined on a Buchi 353 melting-point apparatus. The purities of the target compounds were detected by HPLC, performed on a Waters 1525-2489 (Waters, Milford, MA, USA), with a chromatographic column (Kromasil, C-18, 5 μm, 150 mm × 4.6 mm), at ≥95%. The method conditions were as follows: a mixture of solvents H2O (A) and CH3CN (B) (VA:VB = 5:95) as eluent and a flow rate of 1.0 mL/min. Peaks were detected at λ = 254 nm. NMR spectra were collected on Bruker (Billerica, MA, USA) 400 MHz and 600 MHz instruments, using tetramethylchlorosilane as an internal standard and CDCl3 or DMSO-d6 as solvent. ESI-HRMS spectra were obtained on a Bruker Micromass time of flight mass spectrometer. (7). 2-amino-1-phenylethan-1-one hydrochloride 6 (0.50 g, 2.9 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (13 mL, 8.9 mmol) was added. The mixture was cooled, and 2-chloroacetyl chloride (0.45 g, 4.0 mmol) was added in drops at 0 °C. After 2 h, the solution was recovered to room temperature for 16 h. Then the mixture was poured into water (20 mL) and extracted with dichloromethane (10 mL × 3), and the combined organic layers were washed with water (10 mL × 3) and brine (10 mL × 3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether:ethyl acetate = 4:1) to give 7 (0.39 g, 62.9%) as a white solid. 3,4-diOCH 3 2-NO 2 6.36 ± 0.12 Anace a 0.04 ± 0.01 a Used as a positive control; b Considered with no CETP inhibition activity.

In Vitro Metabolic Stability Study
Based on the result of the in vitro CETP inhibitory assay, potent inhibitors 30 and 32 were selected for the in vitro metabolic stability study. As shown in Table 3, compound 30 showed weak stability, with a clearance rate of 48.1 and 121.7 µL/min/mg in human and rat liver microsomes, while compound 32 exhibited acceptable stability, with a clearance rate of 29.8 and 79.3 µL/min/mg in human and rat liver microsomes.

Chemicals and Instruments
All chemicals and reagents were obtained from commercial sources and were used without purification. TLC, performed on silica gel plates (Indicator F-254), was used to monitor the reactions.
2-(Chloromethyl)-5-phenylthiazole (13b). Intermediate 7 (0.30 g, 1.4 mmol) was dissolved in tetrahydrofuran (5 mL), and Lawesson's reagent (0.34 g, 0.80 mmol) was added. The solution was heated at reflux for 4 h and then cooled to room temperature. The solvent was removed under reduced pressure, and the resulting residue was dissolved in ethyl acetate. The solution was washed with water and brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether:ethyl acetate = 10:1) to give 13b (0.10 g, 59.6%) as a white solid.
3-(Chloromethyl)-5-methyl-1-phenyl-1H-pyrazole (13c). In a solution of intermediate 9 (92.1 mg, 0.40 mmol) dissolved in ethanol (5 mL), sodium borohydride (19.0 mg, 0.50 mmol) was added. The mixture was stirred at room temperature for 30 min, and then water was added. The solution was extracted with ethyl acetate, and the combined organic layers were washed with water and brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was dissolved in DMF (2 mL); then thionyl chloride (0.10 mL, 1.4 mmol) was added. After reflux for 1 h, water was added and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether:ethyl acetate = 10:1) to give 13c (66.6 mg, 80.5%) as a white solid.
2-(Chloromethyl)-4-phenylthiazole (13d). The ester function in 11 was reduced with NaBH 4 and reacted subsequently with SOCl 2 to afford 13d, and this operation was the same as the step in the synthetic intermediate 13c. Compound 13d was obtained as a white solid. Yield: 75.9%.
2-(Chloromethyl)-5-phenyl-1,3,4-oxadiazole (13e). A mixture of benzohydrazide (0.50 g, 3.7 mmol), 2-chloroacetic acid (0.35 g, 3.7 mmol), and phosphorus oxychloride (1.0 mL, 11.0 mmol) was added to a three-necked round bottom flask. The solution was heated at reflux for 6 h and then cooled to 0 • C and neutralized to pH 9 with a saturated sodium carbonate aqueous solution. The precipitate was filtered, washed with water, and dried under an infrared lamp. Compound 13e (0.58 g, 81.1%) was obtained as a white solid. (13f). A mixture of benzene-1,2-diamine (2.0 g, 18.0 mmol) and ethyl 2-chloroacetate, (2.6 mL, 24.0 mmol) was dissolved in dilute hydrochloric acid solution (4 mol/L, 16 mL). The solution was heated at 110 • C for 4 h and then cooled to room temperature. The reaction solution was poured into ice water and then neutralized to pH 9 with ammonium hydroxide. The precipitate was filtered, washed with water, and dried under an infrared lamp to obtain compound 13f (2.7 g, 91.3%) was obtained as a white solid. (13g). In a solution of 2-aminophenol (0.50 g, 4.6 mmol) dissolved in chlorobenzene (5 mL), 2-chloroacetyl chloride (0.52 g, 4.6 mmol) and pyridine (0.02 mL) were added. The mixture was stirred at room temperature for 2 h; then p-toluene sulfonic acid (0.08 g, 0.46 mmol) was added. The mixture was heated at reflux for 8 h and then cooled to room temperature. The solvent was removed under reduced pressure, and the resulting residue was dissolved in ethyl acetate (30 mL). The solution was washed with water and brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether:ethyl acetate = 10:1) to give 13g (0.70 g, 90.2%) as a yellow oil.

Metabolic Stability Study
Ten microliters (10 µL, 100 µM/L) of compounds and 80 µL of liver microsomes were mixed and incubated at 37 • C for 10 min, and then 10 µL of NADPH regenerating system was added. Samples were obtained at 0 min, 5 min, 10 min, 20 min, 30 min and 60 min. respectively, and 300 µL stop solution (cold in 4 • C, including 100 ng/mL tolbutamide and 100 ng/mL labetalol) was added to terminate the reaction. After oscillating for 10 min, the plates were centrifuged (4000 rpm) at room temperature for 20 min, and the supernatants were used for analysis.

Conclusions
A series of N,N-disubstituted-4-arylthiazole-2-methylamine derivatives were designed, synthesized, and evaluated for their inhibitory activity against CETP by a BODIPY-CE fluorescence assay. Compounds 30 and 32 displayed substantial CETP inhibitory activity in vitro with IC 50 values of 0.79 ± 0.02 µM and 0.97 ± 0.01 µM, respectively, and demonstrated weak human/rat liver microsome stability. This suggests that compounds 30 and 32 could act as potential CETP inhibitors to be used for further optimization.