αvβ6; Integrins αvβ6 (KD = 5.7 nM) and αvβ1 (KD = 3.4 nM)

In precision sectioned lung sections (PCLS), bexotegrast (PLN-74809; 1.82 µM; intestinal 7 days) significantly decreased collagen type I alpha I (COL1A1) mRNA expression by 54%. There is less Smad2 phosphorylation in bexotegrast. In PCLS produced from fibrotic lungs, bexotegrast (1.82 µM; workstation 3 days) self-regulates up to a 71% reduction in Col1a1 mRNA expression [2]. αvβ6 integrin is totally blocked by bexotegrast. Approximately 50%[2]. LAP is labeled by normal human epithelial cells with an IC50 of 39.3 nM[2].

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Inhibiting TGF - β activation: Bexotegrast (PLN - 74809) can block multiple TGF - β activation pathways in fibrotic lung cells by inhibiting integrins αvβ6 and αvβ1. It can reduce the expression of type I collagen gene by inhibiting the activation of TGF - β [1]

Bexotegrast (PLN-74809; sidewall; 100, 250, 500 mg/kg; twice daily; from day 7 to day 21) was provided at levels necessary to inhibit bleomycin-challenged cartilage interstitial fibrillar collagen deposition. Bexotegrast dosage.

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Anti - fibrotic effect: In bleomycin - challenged mice, Bexotegrast (PLN - 74809) can dose - dependently inhibit pulmonary Smad3 phosphorylation and collagen deposition, reducing pulmonary fibrosis burden. It has a better antifibrotic effect than nintedanib or pirfenidone, and can more effectively reduce collagen gene expression in fibrotic mouse lung tissue [2]

Animal/Disease Models: C57BL/6 mice [2]
Doses: 100, 250, 500 mg/kg
Route of Administration: Oral; strongly bursts Smad3 phosphorylation [2]. twice (two times) daily; from day 7 to day 21
Experimental Results: There was a dose-dependent significant reduction in interstitial fibrillar collagen deposition in mice challenged with bleomycin (3 units/kg). Dose-dependent blockade of Smad3 phosphorylation.

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Bleomycin - induced lung fibrosis mouse model: Use bleomycin to induce lung fibrosis in mice. Then, administer Bexotegrast (PLN - 74809) to the mice, and set up different dose - groups. After a certain period of treatment, sacrifice the mice, collect lung tissues, and detect the changes of pulmonary collagen deposition and Smad3 phosphorylation, so as to evaluate the antifibrotic effect of the drug [2]

Pharmacokinetics [Am J Respir Crit Care Med. 2024 Aug 15; 210(4):424-434.]
Total and free exposures of bexoglutracet in patients with IPF (maximum concentration and area under the concentration-time curve from 0 to 24 hours after administration) increased approximately proportionally with dose (see Tables E3 and E4).

Safety and Tolerability at Week 12 [Am J Respir Crit Care Med. Aug 15, 2024; 210(4):424-434.]
Overall, bexoglutrast demonstrated good safety and tolerability during 12 weeks of treatment (see Tables 2, 3, E1, and E2 in the online supplemental materials). Most treatment-emergent adverse events (TEAEs) that occurred during treatment were mild or moderate. The most common TEAEs are shown in Table 2. Diarrhea was the most common TEAE, occurring in 15 subjects (16.9%) in the bexoglutrast (pooled) group and in 3 subjects (9.7%) in the placebo group. Of the subjects who reported diarrhea, 13 out of 15 (86.7%) in the bexoglucopyrax group were receiving background treatment with nintedanib, and 1 out of 3 (33.3%) in the placebo group were receiving background treatment with nintedanib; one (6.7%) subject in the bexoglucopyrax group experienced diarrhea while taking pirfenidone (Table 3). Another subject receiving bexoglucopyrax monotherapy who experienced diarrhea had a history of ulcerative colitis. Most diarrheal events (14 out of 15; 93.3%) were mild to moderate; one subject receiving both bexoglucopyrax and pirfenidone experienced grade 3 diarrhea. Four subjects discontinued bexoglucopyrax treatment due to complications of coronavirus disease (COVID-19) (n = 1), diarrhea (n = 2), and bowel obstruction and acute kidney injury (n = 1). Two subjects discontinued bexoglucopyrlast due to mild diarrhea (n = 1, receiving nintedanib; n = 1, not receiving any basic treatment and with a history of ulcerative colitis). Dosage reduction of bexoglucopyrlast was not permitted according to the protocol. No serious adverse events related to the study drug were assessed. In the bexoglucopyrlast group, 2.3% of subjects reported treatment-emergent adverse events (TEAEs) for idiopathic pulmonary fibrosis/pulmonary fibrosis, compared to 9.7% in the placebo group. Only one case was an acute exacerbation of idiopathic pulmonary fibrosis, which occurred 11 days after the last dose in a subject who had completed 12 weeks of 160 mg bexoglucopyrlast. This event was considered drug-independent and resolved the following day after hospitalization for corticosteroids and antibiotics. In the 320 mg bexostat group, a subject with stage III idiopathic pulmonary fibrosis, a history of coronary artery disease, and chronic refractory atrial fibrillation experienced a serious and fatal acute respiratory failure adverse event following elective atrioventricular node ablation. The study drug did not cause significant changes in laboratory parameters, vital signs, physical examination results, or electrocardiogram results. Overall, bexostat was well tolerated when used in combination with IPF background therapy or as monotherapy (Tables 3, E1, and E2).

[1]. De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8. Nat Commun. 2023 Sep 13;14(1):5660.

[2]. Dual inhibition of αvβ6 and αvβ1 reduces fibrogenesis in lung tissue explants from patients with IPF. Respir Res. 2021 Oct 19;22(1):265.

αv integrins are key regulators of TGF-β activation and fibrosis in pulmonary fibrosis models. αvβ6 and αvβ1 are highly expressed in the lung tissue of patients with idiopathic pulmonary fibrosis (IPF) but are expressed at very low levels in normal tissues. Bessogaster (PLN-74809) is a small molecule oral drug that blocks the activation of TGF-β by αvβ6 and αvβ1 and may slow or even stop the fibrosis process in patients with IPF. Currently, a phase II/III clinical trial of PLN-74809 for the treatment of IPF is underway [2]. PLN-74809 is a small molecule drug that can simultaneously inhibit αvβ6 and αvβ1 for the treatment of IPF and primary sclerosing cholangitis (PSC). This compound was granted orphan drug designation by the US FDA in August 2018 for the treatment of idiopathic pulmonary fibrosis (IPF). Pliant Therapeutics recently completed a $100 million Series C financing round to support further clinical development of the compound. Currently, a Phase IIa clinical trial (NCT04396756) is being conducted in 10 participating countries to evaluate the safety and efficacy of PLN-74809 in patients with IPF and primary sclerosing cholangitis (PSC). The clinical trial number is NCT04480840. In addition, this compound is also currently undergoing a Phase IIa clinical trial (NCT04565249) for the treatment of COVID-19-related acute respiratory distress syndrome.

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Drug Indications
PLN-74809 reduces subsequent activation of TGF-β1 by dually inhibiting integrins αvβ6 and αvβ1, and TGF-β1 plays an important role in the growth of fibrotic tissues in the lungs and bile ducts.
Further studies have shown that PLN-74809 can inhibit collagen gene expression in tissues of PSC and IPF patients.

C27H36N6O3

492.61

492.28

C, 65.83; H, 7.37; N, 17.06; O, 9.74

2376257-44-0

2376264-69-4 (R-isomer); 2376257-44-0;2775365-40-5 (HCl);2775365-33-6 (fumarate); 2775365-31-4 (phosphate);

135390719

White to off-white solid powder

1.8

3

9

14

36

655

1

COCCN(CCCCC1=NC2=C(CCCN2)C=C1)CC[C@@H](C(=O)O)NC3=NC=NC4=CC=CC=C43

CWOFQJBATWQSHL-DEOSSOPVSA-N

InChI=1S/C27H36N6O3/c1-36-18-17-33(15-5-4-8-21-12-11-20-7-6-14-28-25(20)31-21)16-13-24(27(34)35)32-26-22-9-2-3-10-23(22)29-19-30-26/h2-3,9-12,19,24H,4-8,13-18H2,1H3,(H,28,31)(H,34,35)(H,29,30,32)/t24-/m0/s1

(S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid

PLN-74809; PLN 74809; PLN-74,809; Bexotegras; Bexotegras [INN]; (S)-4-((2-Methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid; (S)-4-[(2-Methoxyethyl)[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]amino]-2-(quinazolin-4-ylamino)butanoic Acid; Bexotegrast; 2376257-44-0; QCV154PFT4; PLN74809; Bexotegrast; Bexotegrast free base,

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

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

DMSO : 250 mg/mL (507.50 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.22 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 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 20.8 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: ≥ 2.08 mg/mL (4.22 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.22 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 20.8 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.)