LXRα (IC50 = 68 nM); LXRβ (IC50 = 14 nM)

In human whole blood, the ATP-binding transporters ABCA1 and ABCG1 were found to be strongly induced by the LXR selective partial agonist BMS-779788 (EC50=1.2 μM, 55% effectiveness) [2].

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In an effort to improve the potency of the molecules, alternatives to the phenyl substitution were prepared leading to the benzylic imidazoles such as 16 and 17, which both had improved LXRβ agonist potency. Further investigation of the benzylic substitutions afforded the gem-dimethyl analog 18/BMS-779788. These benzyl imidazoles maintained moderate LXRβ binding selectivity and 15–38% partial LXRα agonist efficacy with 43–72% efficacy at LXRβ (Table 2). Importantly 18/BMS-779788 had improved potency in the ABCA1 hWBA (EC50 = 1.2 μM) with partial efficacy (55%), which compares favorably with 2a (hWBA EC50 = 4.6 μM, 56%). As well 18/BMS-779788 is a highly selective LXR agonist when tested against a panel of 14 NHRs at 10 μM, displaying agonist activity only for PXR (EC50 = 2 μM).

BMS-779788 has a similar potency to that of its in vitro blood gene induction when it comes to inducing LXR target genes in blood in vivo (EC50=610 nM). When it came to increasing plasma triglycerides and LDL cholesterol, BMS-779788 was shown to be 29 and 12 times less powerful than the full agonist T0901317, respectively. Similar results were observed for plasma cholesteryl ester transfer protein and apolipoprotein B [1]. BMS-779788 showed better induction than full agonists by peripherally inducing ABCA1 in mice at doses of 3 and 10 mpk without causing appreciable increases in plasma or liver triglycerides at these levels. circumstances [2].

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Liver X Receptors (LXRs) α and β are nuclear hormone receptors that regulate multiple genes involved in reverse cholesterol transport (RCT) and are potential drug targets for atherosclerosis. However, full pan agonists also activate lipogenic genes, resulting in elevated plasma and hepatic lipids. We report the pharmacology of BMS-779788 [2-(2-(1-(2-chlorophenyl)-1-methylethyl)-1-(3'-(methylsulfonyl)-4-biphenylyl)-1H-imidazol-4-yl)-2-propanol], a potent partial LXR agonist with LXRβ selectivity, which has an improved therapeutic window in the cynomolgus monkey compared with a full pan agonist. BMS-779788induced LXR target genes in blood in vivo with an EC50 = 610 nM, a value similar to its in vitro blood gene induction potency. BMS-779788 was 29- and 12-fold less potent than the full agonist T0901317 in elevating plasma triglyceride and LDL cholesterol, respectively, with similar results for plasma cholesteryl ester transfer protein and apolipoprotein B. However, ABCA1 and ABCG1 mRNA inductions in blood, which are critical for RCT, were comparable. Increased liver triglyceride was observed after 7-day treatment with BMS-779788 at the highest dose tested and was nearly identical to the dose response for plasma triglyceride, consistent with the central role of liver LXR in these lipogenic effects. Dose-dependent increases in biliary cholesterol and decreases in phospholipid and bile acid occurred in BMS-779788-treated animals, similar to LXR agonist effects reported in mouse. In summary, BMS-779788, a partial LXRβ selective agonist, has decreased lipogenic potential compared with a full pan agonist in cynomolgus monkeys, with similar potency in the induction of genes known to stimulate RCT. This provides support in nonhuman primates for improving LXR agonist therapeutic windows by limiting LXRα activity.[2]

Human whole blood assays. Human whole blood was collected in EDTA containing tubes and 0.5 mL aliquots were immediately mixed in a 96 well block with the appropriate dilution of test compound/BMS-779788, in 0.5% DMSO. Samples were incubated at 37 °C with constant rotation for 4 h. Following cell lysis, total RNA was purified, cDNAs were synthesized, and mRNAs were quantitated using SYBR-Green Quantitative PCR (Q-PCR) on an ABI Prism 7900HT Sequence Detection System.[2]

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The binding affinities were determined individually for LXRα and LXRβ utilizing a scintillation proximity binding assay that employs RXRα-LXRα, and RXRα-LXRβ heterodimers expressed in insect cells. Isoform selective agonist activities were assessed in transactivation assays in which LXRα or LXRβ were co-transfected in CV-1 cells with the luciferase reporter LXREx1-tk-luc. In order to observe the overall effects on gene transcription, compounds were profiled using endogenous LXRα and LXRβ receptors in an ABCA1 LXREx3 reporter assay in HeLa cells. HeLa cells were transfected with ABCA1x3-tk-luc reporter and pCMXβ galactosidase plasmids and assayed for luciferase activity as described above[2].

Study Design: [1]
The study utilizes male cynomolgus monkeys.
Single-Dose PK-PD Study:
Two animals each receive either a vehicle control (0.5% carboxymethyl cellulose and 2% Tween 80 in purified water) or 1 mg/kg BMS-779788.

7-Day PD Study:
Eighteen animals (3–6 kg) are randomized into six treatment groups (N=3 per group). From day 1 to day 7, each group receives daily oral gavage at 7 AM with one of the following treatments:
Vehicle control
10 mg/kg/day T0901317
0.3, 1, 3, or 10 mg/kg/day BMS-779788

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Mice were dosed (n = 3) by oral gavage with suspension dosing of drug BMS-779788 in 0.75% CMC/0.1% Tween 80 in water. [2]

Mice (C57BL/6) were dosed in vehicle containing 0.75% carboxymethyl cellulose and 0.1% Tween 80 in deionized water for 7 days. ABC transporter mRNA was measured at 5 h post dose last dose. Triglycerides and liver SREBP1c and FAS mRNAs were measured at 24 h post last dose. Pan-agonist 3c was used as a control in the experiment.[2]

Compounds 16 and 18/BMS-779788 both showed high 4-hour plasma exposure (5–6 μM) and low 24-hour liver exposure in mouse pharmacokinetic studies (Table 3), indicating that they do not remain in the liver for long periods, thereby leading to increased hepatic triglyceride production. [2]

[1]. Pharmacological characterization of a novel liver X receptor agonist with partial LXRα activity and a favorable window in nonhuman primates. J Pharmacol Exp Ther. 2015 Feb;352(2):305-14.

[2]. Liver X receptor (LXR) partial agonists: biaryl pyrazoles and imidazoles displaying a preference for LXRβ. Bioorg Med Chem Lett. 2015 Jan 15;25(2):372-7.

BMS-779788 is a small molecule drug currently in Phase I clinical trials with one investigational indication. A series of biarylpyrazole and imidazole hepatic X receptor (LXR) partial agonists have been synthesized, exhibiting selectivity for LXRβ. Among them, the LXRβ selective partial agonist 18 was identified as effectively inducing the expression of ATP-binding transporters ABCA1 and ABCG1 in human whole blood (EC50 = 1.2 μM, 55% efficacy). In mice, compound 18 showed peripheral ABCA1 induction at 3 and 10 mpk doses without significantly increasing plasma or hepatic triglyceride levels at these doses, demonstrating superior properties compared to full pan-agonists. [2]

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Based on its potency against hWBA, partial LXRα agonism, and LXRβ selectivity, mice were administered compound 18/BMS-779788 for 7 consecutive days at doses of 0.3, 1, 3, 10, and 30 mpk/day to assess the induction of ABCA1 and ABCG1 hematopoietic genes and plasma and liver triglyceride levels (Figure 3). ^{37, 38} Significant ABCA1 induction was observed at doses of 3, 10, and 30 mpk, and a similar pattern was observed for ABCG1, with 5-hour drug exposures of 0.05, 0.20, and 2.0 μM, respectively. The EC50 value for ABCA1 expression in whole blood induced in vitro in mice was 0.12 μM, similar to the plasma drug exposure required for in vivo induction of ABCA1 expression. Both 3 and 10 mpk doses of 18/BMS-779788 significantly induced ABCA1 mRNA expression without causing a significant increase in plasma or liver triglyceride levels. Only at the 30 mpk dose did plasma triglyceride levels increase significantly by 74-108%, while no significant increase in liver triglyceride levels was observed at any dose compared to the control pan-agonist, although liver triglyceride levels in the control pan-agonist were 4.8-fold higher than in the solvent control group. The reduced adipogenic properties of 18/BMS-779788 may be due to weakened induction of LXR target genes SREBP1c and FAS in the liver. In the liver, compared to the vector control group, SREBP1c expression was significantly upregulated by 2.7-fold and 3.5-fold at 10 mpk and 30 mpk doses, respectively, while the upregulation in the 3c treatment group was 7.7-fold; no significant change was observed in FAS at the 30 mpk dose. [2]

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These adverse effects on plasma lipids have been a major obstacle to the development of LXR agonist therapies. LXRα is likely the subtype that mediates most of the hepatic effects, at least in mice, as LXRα knockout mice show reduced lipogenesis responses to pan-agonists (Lund et al., 2006; Quinet et al., 2006). Furthermore, pan-agonists of LXR inhibit atherosclerosis in these mice, suggesting that LXRβ is sufficient to produce beneficial effects (Bradley et al., 2007). Therefore, one approach to limiting lipogenesis is to selectively target LXRβ. However, this approach has not been adequately validated in primates. This article reports the pharmacological study of a novel partial LXRβ selective agonist, BMS-779788, in cynomolgus monkeys. Compared to the full pan-agonist, this compound exhibits reduced lipogenesis potential while maintaining similar induction of genes known to enhance RCTs. [1]

C28H29CLN2O3S

509.0595

508.158

C, 66.06; H, 5.74; Cl, 6.96; N, 5.50; O, 9.43; S, 6.30

918348-67-1

59251511

White to off-white solid powder

1.2±0.1 g/cm3

738.7±70.0 °C at 760 mmHg

400.6±35.7 °C

0.0±2.6 mmHg at 25°C

1.605

4.85

1

4

6

35

819

0

ClC1=C([H])C([H])=C([H])C([H])=C1C(C([H])([H])[H])(C([H])([H])[H])C1=NC(=C([H])N1C1C([H])=C([H])C(C2C([H])=C([H])C([H])=C(C=2[H])S(C([H])([H])[H])(=O)=O)=C([H])C=1[H])C(C([H])([H])[H])(C([H])([H])[H])O[H]

JLPURTXCSILYLW-UHFFFAOYSA-N

InChI=1S/C28H29ClN2O3S/c1-27(2,23-11-6-7-12-24(23)29)26-30-25(28(3,4)32)18-31(26)21-15-13-19(14-16-21)20-9-8-10-22(17-20)35(5,33)34/h6-18,32H,1-5H3

2-(2-(2-(2-chlorophenyl)propan-2-yl)-1-(3'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)-1H-imidazol-4-yl)propan-2-ol

XL-652; XL652; BMS-779,788; 918348-67-1; BMS 788; FB7ZTJ8M8A; XL-014; EXEL 04286,652; EXEL-04286,652; XL652; EXEL 04286652; EXEL04286652; EXEL-04286652; BMS-779788; BMS 779788; BMS779788; BMS-788; BMS 788; BMS788

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~196.44 mM)

Solubility in Formulation 1: 2.5 mg/mL (4.91 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.91 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)