PIPE-791
PIPE-791 is an orally active, blood-brain barrier-permeable selective antagonist of LPAR1. PIPE-791 inhibits LPA-induced calcium mobilization, collagen expression, histamine release, and the activation of fibroblasts, microglia and macrophages. PIPE-791 induces oligodendrocyte precursor cell differentiation, myelination and remyelination, and increases the number of microglia in the retina of normotensive rats. PIPE-791 protects mature oligodendrocytes from cytokine-induced death, reduces the levels of pulmonary fibrosis markers and alleviates neuroinflammation in preclinical models. PIPE-791 can be used in the research of glaucoma, neuroinflammatory diseases, chronic osteoarthritis pain, idiopathic pulmonary fibrosis and multiple sclerosis.
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- No. CAS: 2901868-37-7
- Fòrmula: C24H29F2N3O5
- Peso molecular:477.50
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Actividad biológica
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LPA1 Receptor |
IL-1β |
CYP3A4 |
CYP2C8 |
PIPE-791 can bind strongly to the cell membrane of human LPAR1 overexpressing cells, with a Ki value of 0.752 nM and a Kd value of 0.341 nM; it can also inhibit LPA-induced calcium mobilization in human LPAR1 overexpressing cells, and its efficacy increases with pre-incubation time, with IC50 decreasing from 91.8 nM to 9.9 nM[2].
PIPE-791 (100 pM-10 μM; 3 h) acts as a selective LPAR1 antagonist in transiently transfected HEK293T cells, with an LPAR1 IC50 value of 8.0 nM[2].
PIPE-791 exhibits inhibitory activity against PDE3A with an IC50 of 9.0 μM; it also acts as a partial agonist for CNR1 with an EC50 of 15.1 μM, and shows no significant activity against most other screened targets[2].
PIPE-791 induces CYP3A4 in cryopreserved human hepatocytes with an EC50 of 25.6 μM; it directly and time-dependently inhibits CYP2C8, with IC50 values of 17.4 μM and 7.73 μM[2].
PIPE-791 inhibits OATP1B1 (IC50 = 3.5 μM), OAT3 (IC50 = 23.0 μM), OATP1B3 (IC50 = 20.7 μM) and BSEP (IC50 = 24.4 μM), and shows no obvious inhibitory activity against most other tested human transporters. Its IC50 value against LPAR1 reaches 8 nM in HEK293T cells. It potently suppresses LPA-triggered chemotaxis (IC50 = 1.5 nM) and COL1A1 expression (IC50 = 1.1 nM) in primary adult pulmonary fibroblasts. Besides, it blocks myofibroblast transformation induced by TGFβ1 or LPA[2].
PIPE-791 (0.03-3 µM; 48 h-6 days) reduces the expression of key fibrotic genes (COL1A1, COL3A1, SERPINE1, TIMP1) in 6-day cultures of precision-cut lung slices (PCLS) derived from pulmonary fibrosis donors, and decreases the levels of secreted C3M and Pro-C6 biomarkers in 48-hour cultures of fresh PCLS derived from pulmonary fibrosis donors[3].
PIPE-791 potently binds to human LPA1 receptors in recombinant membranes, with a Ki value of 0.752 nM and an IC50 value of 2.63 nM. It binds to LPA1 receptors in native human brain homogenate with a Kd value of 0.68 nM, and binds to LPA1 receptors in native mouse brain homogenate with a Kd value of 1.7 nM[4].
PIPE-791 induces the differentiation of primary rat O4+ oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes in a dose-dependent manner, with an EC50 of 108 nM; it promotes functional myelination of axons by oligodendrocytes in primary rat cortical culture systems, with an EC50 of 2.6 nM[4].
PIPE-791 (300 nM; 48 h) reverses the inhibitory effect of macrophages on the differentiation of primary rat oligodendrocyte precursor cells (OPC)[4].
PIPE-791 (3 μM; 2 h pre-incubation, 3 h with LPA) inhibits lysophosphatidic acid (LPA)-induced activation of microglia and maintains their branched morphology in hippocampal slices from postnatal day 20 mice[4].
PIPE-791 (0.001 μM-3 μM; 72 h) dose-dependently protects mature rat oligodendrocytes against TNFα/IFNγ-induced cell death, with an EC50 of 125 nM[4].
PIPE-791 (0.001 nM-1 μM; 72 h, 5 days) promotes remyelination in postnatal day 17 mouse cortical slices demyelinated by lysophosphatidylcholine, with an EC50 value of 12.1 nM for Mbp transcript induction, 74 nM for the increase in MBP-positive areas, and 17.9 nM for the increase in Caspr punctate structure count[4].
PIPE-791 (0.3 nM-300 nM; 9 days) dose-dependently induces oligodendrocyte differentiation in adult cortical slices, with an EC50 of 4.2 nM for inducing Mbp transcripts, and the number of CC1+ oligodendrocytes increases significantly at 300 nM[4].
PIPE-791 (0.001 nM-1 μM; 15 h+5 h for rat cells, 6 h+4 h for human cells) inhibits lysophosphatidic acid (LPA)-induced activation of rat and human meningeal fibroblasts, with IC50 values of 31.8 nM and 4.5 nM, respectively[4].
PIPE-791 inhibits LPS-induced IL-1β secretion in primary human alveolar macrophages in vitro[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
PIPE-791 (0.03-3 mg/kg; p.o.; daily administration; for 15 consecutive days) dose-dependently improves body weight, increases survival rate, and reduces the levels of multiple fibrosis markers and pulmonary collagen in a mouse model of pulmonary fibrosis induced by oropharyngeal administration of Bleomycin (HY-108345)[3].
PIPE-791 (3 mg/kg; p.o.; once daily; for 29 consecutive days) reduces pulmonary collagen levels to those of the control group in a mouse model of subcutaneous Bleomycin-induced chronic pulmonary fibrosis[3].
PIPE-791 (0.003-3 mg/kg; p.o.; single administration or daily administration for 4 consecutive days) exhibits long-term LPAR1 receptor binding kinetics in healthy mice. Its receptor occupancy potency at 24 h after single administration is 20-fold higher than that at 3 h, and receptor occupancy can be maintained at steady state at low doses[3].
PIPE-791 (3 mg/kg; p.o.; single administration) increases mature oligodendrocytes in healthy mice by 163%[4].
PIPE-791 (0.03-3 mg/kg; p.o.; single dose/once daily; up to 4 days) achieves dose-dependent, long-lasting LPA1 receptor occupancy in mouse brains, with an ED50 of 0.17-0.19 mg/kg for a single dose and an ED50 of 0.03 mg/kg at steady state. Moreover, receptor occupancy persists for up to 7 days after a single 3 mg/kg dose[4].
PIPE-791 (3 mg/kg; p.o.; once daily; for 11 consecutive days) reduces Bleomycin-induced macrophage activation and IL-1β secretion in a mouse model of pulmonary fibrosis established by intratracheal injection of Bleomycin[3].
PIPE-791 (0.3-3 mg/kg; p.o.; single administration or daily administration for 4 days) dose-dependently inhibits LPA-induced mast cell histamine release in healthy mice, with the pharmacodynamic effect lasting for 24 hours after administration and enhanced under steady-state conditions[3].
PIPE-791 (0.3-3 mg/kg; p.o.; once daily; for 25 consecutive days) significantly reduces disease severity, improves myelination, restores visual evoked potential latency, and decreases microglial activation in MOG-EAE mouse models of multiple sclerosis[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Sprague-Dawley, Göttingen minipigs (male and female)[2]
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Dosage:30 mg/kg/day; 100 mg/kg/day; 1000 mg/kg/day
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Administration:p.o.; daily; 28 days
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Result:Observed no test article-related mortality or adverse findings at any dose.
Observed no signals of hepatobiliary toxicity or neurotoxicity, even at the 1000 mg/kg/day dose.
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Animal Model:C57BL6/N (female, 8-10 weeks old, oropharyngeal bleomycin-induced pulmonary fibrosis)[3]
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Dosage:0.03 mg/kg; 0.3 mg/kg; 3 mg/kg
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Administration:p.o.; daily; 15 days
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Result:Improved body weight by 28% compared to bleomycin/vehicle controls at 0.03 mg/kg.
Improved body weight by 41% compared to bleomycin/vehicle controls at 0.3 mg/kg.
Improved body weight by 38% compared to bleomycin/vehicle controls at 3 mg/kg.
Prevented deaths in all dosed groups, compared to 3 deaths in the bleomycin/vehicle group.
Reduced BALF procollagen by 65%, TGFβ1 by 51%, and TIMP1 by 57% compared to bleomycin/vehicle controls at 3 mg/kg.
Reduced lung hydroxyproline by 41% compared to bleomycin/vehicle controls at 0.3 mg/kg.
Reduced lung hydroxyproline by 39% compared to bleomycin/vehicle controls at 3 mg/kg.
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Animal Model:C57BL/6 (female, 9 weeks old, subcutaneous bleomycin-induced chronic pulmonary fibrosis)[3]
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Dosage:3 mg/kg
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Administration:p.o.; daily; 29 days
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Result:Reduced bleomycin-induced lung tissue collagen fraction to levels comparable to vehicle/vehicle controls, with a significant reduction compared to bleomycin/vehicle controls.
Reduced bleomycin-induced lung hydroxyproline levels by 40% compared to bleomycin/vehicle controls, with levels not significantly different from vehicle/vehicle controls.
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Animal Model:CD-1 (female, intratracheal bleomycin-induced pulmonary fibrosis)[3]
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Dosage:3 mg/kg
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Administration:p.o.; daily; 11 days
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Result:Reduced bleomycin-induced macrophage size (measured by CD68 area) by 56% compared to bleomycin/vehicle controls.
Reduced bleomycin-induced IL-1β levels in BAL fluid by 69.2% compared to bleomycin/vehicle controls.
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Animal Model:CD-1 (female)[3]
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Dosage:0.3 mg/kg; 3 mg/kg
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Administration:p.o.; single dose or daily; 4 days
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Result:Significantly blocked histamine release at both 3 and 24 hours post-dose at 3 mg/kg single dose.
Significantly blocked histamine release at 24 hours but not 3 hours post-dose at 0.3 mg/kg single dose.
Significantly blocked histamine release at both 3 and 24 hours after the final dose at both 0.3 mg/kg and 3 mg/kg with 4 daily doses.
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Animal Model:C57BL6/N (female, single-dose occupancy)
C57BL/6 (female, steady-state occupancy)[4] -
Dosage:0.03-1 mg/kg (single-dose/steady-state occupancy); 3 mg/kg (extended occupancy time course)
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Administration:p.o.; single dose (assessed 2 h or 24 h post-dose, single-dose/extended occupancy); p.o.; once daily; 4 consecutive days (assessed 2 h after fourth dose, steady-state occupancy)
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Result:Achieved dose-dependent LPA1 receptor occupancy with an ED50 of 0.17 mg/kg (assessed 2 h post-dose) and 0.19 mg/kg (assessed 24 h post-dose); unbound brain EC50 was 2.2 nM.
Reduced the ED50 to 0.03 mg/kg at steady state, with an unbound brain EC50 of 2.4 nM.
Sustained LPA1 occupancy for 24 h after a single 3 mg/kg dose, with occupancy slowly decreasing over 7 days, while plasma concentrations peaked at 2 h and were undetectable after 3 days.
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Animal Model:C57BL/6 (female, 12 per treatment group, MOG35-55/CFA emulsion + pertussis toxin-induced multiple sclerosis model)[4]
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Dosage:0.3 mg/kg; 3 mg/kg
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Administration:p.o.; once daily; 25 consecutive days
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Result:Significantly mitigated body weight loss relative to vehicle; cumulative body weight was significantly increased in both treatment groups (0.3 mg/kg: p=0.0126; 3 mg/kg: p=0.0003).
Delayed disease onset to Day 14 in both treatment groups; peak clinical scores reached 2.1 (0.3 mg/kg) and 1.4 (3 mg/kg) compared to 3.2 in vehicle-treated mice; cumulative disease index was significantly reduced at 3 mg/kg (p=0.0092), with a trending improvement at 0.3 mg/kg (p=0.0575).
Shortened N1 latencies to 54.6 ms (0.3 mg/kg) and 52 ms (3 mg/kg) compared to 60.9 ms in vehicle-treated mice (non-EAE control latency: 56.4 ms).
Increased myelinated axons (g-ratio <1) in spinal cord to 83.3% (0.3 mg/kg) and 84.6% (3 mg/kg) compared to 73.4% in vehicle-treated mice (non-EAE control: 90.9%); increased thinly myelinated axons (1 > g-ratio ≥0.8) in spinal cord to 32.3% (0.3 mg/kg) and 31.9% (3 mg/kg) compared to 23.6% in vehicle-treated mice (non-EAE control: 31.2%).
Increased myelinated axons (g-ratio <1) in optic nerve to 85.5% (0.3 mg/kg) and 86.1% (3 mg/kg) compared to 68.7% in vehicle-treated mice (non-EAE control: 86.4%); increased thinly myelinated axons (1 ≥ g-ratio ≥0.8) in optic nerve to 44.7% (0.3 mg/kg) and 50.6% (3 mg/kg) compared to 30.2% in vehicle-treated mice (non-EAE control: 50.7%).
Significantly reduced IBA1 staining (marker of activated microglia) in the 3 mg/kg treatment group relative to vehicle-treated mice.
Chemical Information
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No. CAS 2901868-37-7
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Peso molecular 477.50
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Fòrmula C24H29F2N3O5
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SMILES
COC1=NC(OC(F)F)=C(NC(N([C@@H]2CC[C@@H](C(O)=O)CC2)C3=CC=CC=C3C(C)C)=O)C=C1
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
[1]. Kocherlakota S, et al. Pharmacological Blockade of LPAR1 Does Not Provide Neuroprotection in a Rat Model of Ocular Hypertensive Glaucoma. Translational vision science & technology. 2026 Jan 05;15(1):11. [Content Brief]
[2]. Chen A, et al. Discovery of , A Potent and Brain-Penetrant Lysophosphatidic Acid Receptor 1 Antagonist with Slow Tight Binding Characteristics for the Treatment of Neuroinflammatory Disorders. Journal of medicinal chemistry. 2026 Jul 09;69(13):15888-15927. [Content Brief]
[3]. Poon M, et al. The LPAR1 antagonist, PIPE-791 produces antifibrotic effects in models of lung fibrosis. Respiratory research. 2025 Aug 31;26(1):265. [Content Brief]
[4]. Poon MM, et al. Discovery of a brain penetrant small molecule antagonist targeting LPA1 receptors to reduce neuroinflammation and promote remyelination in multiple sclerosis. Scientific reports. 2024 May 08;14(1):10573. [Content Brief]
Calculators
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