BMS-299897 acts as a γ-secretase (γ-secretase) inhibitor, targeting the γ-secretase enzyme complex involved in amyloid precursor protein (APP) processing [1]

BMS-299897 is a selective γ-secretase inhibitor that targets the γ-secretase complex to regulate APP cleavage and amyloid-β (Aβ) peptide production; [2]

Every Aβ peptide has its levels lowered by BMS-299897. BMS-299897 decreased these peptides to 20% to 50% of vehicle control levels at a dose of 1 μM. The QD-BDNF signal's retrograde-moving portion (p=0.0198) was decreased by the BMS-299897 treatment, although its anterograde-moving portion (p=0.0147) increased [2].

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In rat E18 cortical neurons (DIV7) treated with 1μM BMS-299897 for 24 hours: the compound significantly reduced the levels of Aβ peptides (Aβ38, Aβ40, Aβ42) in the culture medium, increased the accumulation of APP C-terminal fragments (APP CTFs), and affected the processing of another γ-secretase substrate (N-cadherin) as detected by Western blotting; real-time PCR analysis showed no significant changes in the mRNA levels of relevant genes compared to the vehicle group [2]

In rat E18 hippocampal neurons treated with 1μM BMS-299897: the compound disrupted the retrograde axonal trafficking of quantum dot-labeled brain-derived neurotrophic factor (QD-BDNF), reducing the average velocity of QD-BDNF movement and altering the directionality of transport (increasing stationary and anterograde fractions while decreasing retrograde fraction); it also suppressed BDNF-induced downstream signaling, including reduced phosphorylation of TrkB (pTrkB), Akt1 (pAkt1), and Erk1/2 (pErk1/2) in both neuronal soma and axons [2]

In rat E18 hippocampal neurons (DIV4) treated with 1μM BMS-299897 every 24 hours until DIV7: the compound altered the distribution of mitochondria (decreased mitochondrial density and abnormal clustering) and synaptophysin-positive synaptic vesicles (reduced density of synaptic vesicle puncta) in neuronal processes, as observed by MitoTracker labeling, immunofluorescence staining, and transmission electron microscopy [2]

In the brain, cerebrospinal fluid (CSF), and plasma of young transgenic mice, BMS-299897 demonstrates a dose- and time-dependent decrease in amyloid beta-peptide (Aβ), with a link between brain and CSF Aβ levels. In APP-YAC mice, BMS-299897 decreased Aβ1-40 in the brain and plasma and raised APP carboxyl-terminal fragment concentrations in the brain, which is consistent with γ-secretase inhibition. BMS-299897 reduces the toxicity and Aβ1-42 seeding caused by Aβ25-35. Aβ25-35 (9 nmol) and BMS-299897 were given to male Swiss mice at a dose of 0.1–1 nmol/mouse concurrently. A week later, the mice's hippocampal lipid peroxidation level and the contents of Aβ1-42 and Aβ1-40 were examined. To assess the short- and long-term memory capacities of mice, experiments including spontaneous alternation, passive avoidance, and object recognition were conducted. Aβ25-35 has no effect on Aβ1-40 but raises the content of Aβ1-42 by +240%. BMS-299897 considerably lowers Aβ1-40 levels and prevents the rise in Aβ1-42 content. The chemical in question has no effect on the rise in hippocampus lipid peroxidation generated by Aβ25-35. Using a 1-hour inter-trial delay, BMS-299897 behaviorally inhibits Aβ25-35-induced spontaneous alternation or impairments in novel object identification. The γ-secretase inhibitor BMS-299897, when administered in conjunction with Aβ25-35, totally prevents the increase in Aβ1-42 content in mice at doses between 0.1 and 1 μmol/mouse [1].

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In male Swiss mice with intracerebroventricular (i.c.v.) injection of aggregated Aβ25-35 (9 nmol) (a mouse model of Alzheimer’s disease): co-administration of BMS-299897 at doses of 0.1–1 nmol/mouse blocked the Aβ25-35-induced 240% increase in hippocampal Aβ1-42 content and significantly reduced hippocampal Aβ1-40 levels after 1 week; however, it did not affect the Aβ25-35-induced increase in hippocampal lipid peroxidation [1]

Behavioral tests in the above mouse model: BMS-299897 (0.1–1 nmol/mouse) reversed Aβ25-35-induced deficits in spontaneous alternation and novel object recognition tests when using a 1-hour intertrial interval; but it failed to improve Aβ25-35-induced impairments in passive avoidance or novel object recognition tests when using a 24-hour intertrial interval [1]

Alzheimer’s disease mouse model establishment and drug administration: Male Swiss mice were used. The model was induced by intracerebroventricular (i.c.v.) injection of an aggregated preparation of Aβ25-35 (9 nmol per mouse). BMS-299897 was administered via i.c.v. injection at doses of 0.1–1 nmol per mouse, concomitantly with the Aβ25-35 injection [1]

Sample collection and biochemical analysis: One week after injection, mice were euthanized. The hippocampus was dissected and homogenized. The homogenates were used to measure the contents of Aβ1-42 and Aβ1-40 (via relevant detection methods) and the level of lipid peroxidation (to assess oxidative stress) [1]

Behavioral testing protocol: Three behavioral tests were conducted one week after injection: 1) Spontaneous alternation test to evaluate short-term working memory; 2) Passive avoidance test to assess long-term associative memory; 3) Novel object recognition test to measure recognition memory. For the novel object recognition test, two intertrial intervals (1 hour and 24 hours) were used to distinguish short-term and long-term memory effects [1]

After treating E18 rat hippocampal neurons with 1 μM BMS-299897 for 3–8 days: continuous treatment resulted in significant changes in neuronal morphology, including reduced cell body volume and decreased dendritic complexity (quantitatively determined by Sholl analysis and primary dendrite number) [2]. After treating E18 rat cortical and hippocampal neurons with 1 μM BMS-299897 for 24 hours: the compound induced BDNF-dependent neurotrophic signal transduction defects (inhibition of pTrkB, pAkt1, and pErk1/2 expression) and abnormal mitochondrial aggregation in neuronal processes, which may impair neuronal function [2].

[1]. The γ-secretase inhibitor 2-[(1R)-1-[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl) amino]ethyl-5-fluorobenzenebutanoic acid (BMS-299897) alleviates Aβ1-42 seeding and short-term memory deficits in the Aβ25-35 mouse model of Alzheimer's d.

[2]. A γ-secretase inhibitor, but not a γ-secretase modulator, induced defects in BDNF axonal trafficking and signaling: evidence for a role for APP. PLoS One. 2015 Feb 24;10(2):e0118379.

4-[2-[(1R)-1-(N-(4-chlorophenyl)sulfonyl-2,5-difluoroaniline)ethyl]-5-fluorophenyl]butyric acid is a sulfonamide.

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BMS-299897 can block Aβ25-35-induced Aβ1-42 dissemination in mouse models, confirming that γ-secretase inhibition can interfere with the accumulation of endogenous Aβ1-42; this indicates that the Aβ25-35 injection mouse model can be used to screen for the activity of novel secretase inhibitors [1]

The detrimental effects of BMS-299897 (e.g., BDNF transport defects, neuronal morphological changes) are APP-dependent: in rat hippocampal neurons, knockdown of APP by specific siRNA can partially rescue BMS-299897-induced QD-BDNF velocity and directionality defects and reverse the inhibition of BDNF-induced pCREB activation [2]

Unlike γ-secretase regulators (GSM, such as sGSM41), BMS-299897 (a γ-secretase inhibitor) increases APP CTF. The accumulation of these substances is related to their neurotoxic effects; this suggests that GSMs may be a safer alternative to γ-secretase inhibitors for the treatment of Alzheimer's disease [2]

C24H21NO4F3SCL

511.94104

511.083

290315-45-6

11249248

White to off-white solid powder

1.4±0.1 g/cm3

620.0±65.0 °C at 760 mmHg

328.7±34.3 °C

0.0±1.9 mmHg at 25°C

1.602

5.28

1

8

9

34

775

1

C[C@H](C1=C(C=C(C=C1)F)CCCC(=O)O)N(C2=C(C=CC(=C2)F)F)S(=O)(=O)C3=CC=C(C=C3)Cl

IZAOBRWCUGOKNH-OAHLLOKOSA-N

InChI=1S/C24H21ClF3NO4S/c1-15(21-11-7-18(26)13-16(21)3-2-4-24(30)31)29(23-14-19(27)8-12-22(23)28)34(32,33)20-9-5-17(25)6-10-20/h5-15H,2-4H2,1H3,(H,30,31)/t15-/m1/s1

(R)-4-(2-(1-(4-chloro-N-(2,5-difluorophenyl)phenylsulfonamido)ethyl)-5-fluorophenyl)butanoic acid

BMS299897; BMS 299897; BMS-299897

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 : ≥ 30 mg/mL (~58.60 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.88 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (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 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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 (Please use freshly prepared in vivo formulations for optimal results.)