Addition of Optimized Bovine Serum Albumin Level in a High-Throughput Caco-2 Assay Enabled Accurate Permeability Assessment for Lipophilic Compounds

Cai, Xianmei; Madari, Shilpa; Walker, Aaron; Paiva, Anthony; Liu, Ying; Herbst, John J.; Shou, Wilson Z.; Weller, Harold N.

doi:10.1177/2472555219848483

Cited by 15 publications

(16 citation statements)

References 15 publications

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“…3-Methoxy-4-(oxazol-5-yl)aniline (67). 5-(2-Methoxy-4nitrophenyl)oxazole (66) (700 mg, 3.18 mmol) was dissolved in EtOH (30 mL) and CHCl 3 (15 mL) in a Parr bottle.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

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Discovery, Structure–Activity Relationships, and In Vivo Evaluation of Novel Aryl Amides as Brain Penetrant Adaptor Protein 2-Associated Kinase 1 (AAK1) Inhibitors for the Treatment of Neuropathic Pain

et al. 2021

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Effective treatment of chronic pain, in particular neuropathic pain, without the side effects that often accompany currently available treatment options is an area of significant unmet medical need. A phenotypic screen of mouse gene knockouts led to the discovery that adaptor protein 2-associated kinase 1 (AAK1) is a potential therapeutic target for neuropathic pain. The synthesis and optimization of structure–activity relationships of a series of aryl amide-based AAK1 inhibitors led to the identification of 59, a brain penetrant, AAK1-selective inhibitor that proved to be a valuable tool compound. Compound 59 was evaluated in mice for the inhibition of μ2 phosphorylation. Studies conducted with 59 in pain models demonstrated that this compound was efficacious in the phase II formalin model for persistent pain and the chronic-constriction-injury-induced model for neuropathic pain in rats. These results suggest that AAK1 inhibition is a promising approach for the treatment of neuropathic pain.

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“…3-Methoxy-4-(oxazol-5-yl)aniline (67). 5-(2-Methoxy-4nitrophenyl)oxazole (66) (700 mg, 3.18 mmol) was dissolved in EtOH (30 mL) and CHCl 3 (15 mL) in a Parr bottle.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Caco-2 Assay. 67,68 Caco-2 cells were seeded on collagen-coated polycarbonate 24-well Transwell plates and cultured to grow for 21 days to form a confluent monolayer. The monolayer integrity was assessed using a transepithelial electric resistance (TEER) before commencing the assay to ensure that it met acceptable criteria (>600 Ω•cm 2 ).…”

Section: Notesmentioning

confidence: 99%

Discovery, Structure–Activity Relationships, and In Vivo Evaluation of Novel Aryl Amides as Brain Penetrant Adaptor Protein 2-Associated Kinase 1 (AAK1) Inhibitors for the Treatment of Neuropathic Pain

et al. 2021

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“…Caco-2 Assay. 53,54 Caco-2 cells were seeded on collagen-coated polycarbonate 24-well transwell plates and cultured to grow for 21 days to form a confluent monolayer. The monolayer integrity was assessed using a transepithelial electric resistance (TEER) before commencing the assay to ensure that it met acceptable criteria (>600 Ω•cm 2 ).…”

Section: ■ Associated Contentmentioning

confidence: 99%

Synthesis, Structure–Activity Relationships, and In Vivo Evaluation of Novel Tetrahydropyran-Based Thiodisaccharide Mimics as Galectin-3 Inhibitors

Hartz

Beno

et al. 2021

J. Med. Chem.

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Galectin-3 is a member of a family of β-galactoside-binding proteins. A substantial body of literature reports that galectin-3 plays important roles in cancer, inflammation, and fibrosis. Small-molecule galectin-3 inhibitors, which are generally lactose or galactose-based derivatives, have the potential to be valuable disease-modifying agents. In our efforts to identify novel galectin-3 disaccharide mimics to improve drug-like properties, we found that one of the monosaccharide subunits can be replaced with a suitably functionalized tetrahydropyran ring. Optimization of the structure–activity relationships around the tetrahydropyran-based scaffold led to the discovery of potent galectin-3 inhibitors. Compounds 36, 40, and 45 were selected for further in vivo evaluation. The synthesis, structure–activity relationships, and in vivo evaluation of novel tetrahydropyran-based galectin-3 inhibitors are described.

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“…Caco-2 Assay. 55,56 Caco-2 cells were seeded on collagen-coated polycarbonate 24-well transwell plates and cultured to grow for 21 days to form a confluent monolayer. The monolayer integrity was assessed using a transepithelial electric resistance before commencing the assay to ensure that it met acceptable criteria (>600 Ω•cm 2 ).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Discovery of (S)-1-((2′,6-Bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211): A Highly Selective, CNS Penetrable, and Orally Active Adaptor Protein-2 Associated Kinase 1 Inhibitor in Clinical Trials for the Treatment of Neuropathic Pain

et al. 2022

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Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been identified and show efficacy in various rodent pain models. (S)-1-((2′,6-Bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211) (34) was identified as a highly selective, CNS penetrant, potent AAK1 inhibitor from a novel class of bi(hetero)aryl ethers. BMS-986176/LX9211 (34) showed excellent efficacy in two rodent neuropathic pain models and excellent central nervous system (CNS) penetration and target engagement at the spinal cord with an average brain to plasma ratio of 20 in rat. The compound exhibited favorable physicochemical and pharmacokinetic properties, had an acceptable preclinical toxicity profile, and was chosen for clinical trials. BMS-986176/LX9211 (34) completed phase I trials with good human pharmacokinetics and minimum adverse events and is currently in phase II clinical trials for diabetic peripheral neuropathic pain (ClinicalTrials.gov identifier: NCT04455633) and postherpetic neuralgia (ClinicalTrials.gov identifier: NCT04662281).

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Addition of Optimized Bovine Serum Albumin Level in a High-Throughput Caco-2 Assay Enabled Accurate Permeability Assessment for Lipophilic Compounds

Cited by 15 publications

References 15 publications

Discovery, Structure–Activity Relationships, and In Vivo Evaluation of Novel Aryl Amides as Brain Penetrant Adaptor Protein 2-Associated Kinase 1 (AAK1) Inhibitors for the Treatment of Neuropathic Pain

Discovery, Structure–Activity Relationships, and In Vivo Evaluation of Novel Aryl Amides as Brain Penetrant Adaptor Protein 2-Associated Kinase 1 (AAK1) Inhibitors for the Treatment of Neuropathic Pain

Synthesis, Structure–Activity Relationships, and In Vivo Evaluation of Novel Tetrahydropyran-Based Thiodisaccharide Mimics as Galectin-3 Inhibitors

Discovery of (S)-1-((2′,6-Bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211): A Highly Selective, CNS Penetrable, and Orally Active Adaptor Protein-2 Associated Kinase 1 Inhibitor in Clinical Trials for the Treatment of Neuropathic Pain

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