Method for improving health of digestive organ

Abstract

To provide a method for improving the health of a digestive organ by providing an ingestible composition.SOLUTION: A method includes a step of providing an ingestible composition containing a compound of formula (I), or an effective amount of extract containing an isomer, a salt, a homodimer, a heterodimer or a conjugate thereof, and thus improving the health of a digestive organ.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to methods for improving digestive health. [Background technology]

[0002] HNF4α is a nuclear receptor that acts as a transcriptional regulator of many genetic programs in humans, including those underlying glucose and lipid metabolism. It is expressed in several tissues, including the liver, pancreas, kidney, and intestine. HNF4α is known to play diverse roles in epithelial biology, including central regulation of epithelial morphogenesis and in the homeostasis and barrier function of the intestinal epithelium (Cattin et al. (2009) Mol. Cell. Biol. 29(23):6294-6308; Spath and Weiss (1998) J. Cell Biol. 140:935-946). In addition, the HNF4α gene is highly expressed in the small intestine and colon, and HNF4α protein is abundant in the nuclei of mucosal epithelial cells (Jiang et al. (2003) Nucl. Recept. 1:5). Furthermore, it has been suggested that HNF4α has a protective role in inflammatory bowel disease (IBD) and that HNF4α agonists may be used to treat IBD (Chahar et al. (2014) Mol. Cell. Biol. 34:3291-3304). Studies have shown that HNF4α is important for the expression and proper localization of tight and adhesive junction proteins (Chiba et al. (2003) Exp. Cell Res. 286:288-297; Parviz et al. (2003) Nat. Genet. 34:292-296) and the formation of intestinal microvilli (Chiba et al. (2006) J. Cell Biol. 175(6):971-980). Furthermore, HNF4α has also been described as a central regulator of intestinal epithelial protection against inflammation (Babeu and Boudreau (2014) World J. Gastroenterol. 20(1):22-30). Furthermore, HNF4α expression has been shown to be dramatically reduced in intestinal tissue from patients with Crohn's disease (CD) and ulcerative colitis (UC) (Darsigny et al. (2009) PLoS One 4:e7609; Ahn et al. (2008) Inflamm. Bowel Dis. 14:908-920).

[0003] Studies of intestine-specific HNF4α null mice have shown that the null mice are more susceptible to dextran sulfate sodium (DSS)-induced colitis and exhibit increased intestinal permeability compared with control mice (Ahn et al. (2008) Inflamm. Bowel Dis. 14:908-920). Another study showed that mice lacking intestinal expression of both HNF4α P1 and P2 isoforms developed progressive chronic gastrointestinal inflammation similar to human IBD, suggesting that long-term reduction in HNF4α activity may promote IBD (Darsigny et al. (2009) PLoS One 4:e7609). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] WO 2018 / 161077 A1 [Non-patent literature]

[0005] [Non-Patent Document 1] Cattin et al. (2009) Mol. Cell. Biol. 29(23): 6294-6308 [Non-licensed Document 2] Spath and Weiss (1998) J. Cell Biol. 140: 935~946 [Non-licensed Document 3] Jiang et al. (2003) Nucl. Recept. 1:5 [Non-licensed Document 4] Chahar et al. (2014) Mol. Cell. Biol. 34:3291-3304 [Non-licensed Document 5] Chiba et al. (2003) Exp. Cell Res. 286:288-297 [Non-licensed Document 6] Parviz et al. (2003) Nat. Genet. 34:292-296 [Non-licensed Document 7] Chiba et al. (2006) J. Cell Biol. 175(6): 971-980 [Non-licensed Document 8] Babeu and Boudreau (2014) World J. Gastroenterol. 20(1): 22-30 pages [Non-licensed Document 9] Darsigny et al (2009) PLoS One 4:e7609 [Non-licensed Document 10] Ahn et al. (2008) Inflamm. Bowel Dis. 14: 908-920 pages [Non-licensed Document 11] King and Calhoun (2005) Phytochemistry 66(20): 2468~73 [Non-licensed Document 12] Lobov et al. (1991) Agric. Biol. Chem. 55:2959-2965 [Non-licensed Document 13] Kitahata et al. (1989) Agric. Biol. Chem. 53:2923-2928 [Non-licensed Document 14] Yamamoto et al. (1994) Biosci. Biotech. Biochem. 58: pp. 1657~1661 [Non-licensed Document 15] Ko et al. (2015) Internatl. J. Mol. Med. 36(4): 1042-8 [Non-licensed Document 16] Ludidi et al. (2015) PLoS One 10(5):e0123498 [Non-licensed Document 17] Williams et al. (1988) Gastroenterology 94: 611-621 [Non-licensed Document 18] Traini et al. (2016) Neurogastroenterol. Motil. 28:1172-1185 [Non-licensed Document 19] Traini et al. (2017) J. Cell. Mol. Med. 21: 735-745 [Non-licensed Document 20] Okayasu et al. (1990) Gastroenterology 98:694-702 [Non-licensed Document 21] Lee et al. (2013) ACS Chem. Biol. 8 (8): 1730-6 [Non-licensed Document 22] Porter et al. (1999) Br. J. Pharmacol. 128 (1): 13-20 [Non-licensed Document 23] Davison et al. (2017) Genome Res. 27:1195-206 [Non-licensed Document 24] Qin et al (2018) Genome Biol. 19:7 [Non-licensed Document 25] Stenman et al. (2012) World J. Gastroenterol. 18(9): 923-99 [Non-licensed Document 26] Kiselyuk et al. (2010. J. Biomol. Screen 15(6) :663~70) [Non-Patent Document 27] Kiselyuk et al. (2012) Chem. Biol. 19(7) :806~18 [Non-patent document 28] Inoue et al. (2002) J. Biol. Chem. 277:25257~65 Summary of the Invention [Problem to be solved by the invention]

[0006] It is estimated that 3 million American adults, slightly more than 1% of the population, have been diagnosed with IBD, and the prevalence is rising. Direct treatment costs for IBD are estimated to be nearly $7 billion. Because many conditions go undiagnosed and children can also suffer from IBD, the actual prevalence of IBD may be higher and exceed current cost estimates. Therefore, there is a need in the art to improve the digestive health of these individuals in a manner that is highly acceptable to patients, effective, relatively safe, and relatively low cost. The present disclosure addresses this need in the art. [Means for solving the problem]

[0007] The present disclosure provides methods for improving digestive health by providing an ingestible composition comprising at least one carrier and an effective amount of an extract comprising a compound of formula I or an isomer, salt, homodimer, heterodimer, or conjugate thereof.

[0008] [ka]

[0009] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R6 , R 7 , R 8 , and R 9 are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted -(O)C 1~6 Alkyl, optionally substituted -(O)C 1~6 Alkenyl, optionally substituted -(O)C 1~6 Alkynyl, optionally substituted -(O)C 4~12 Cycloalkyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Cycloalkyl, optionally substituted -(O)C 4~12 Heterocyclyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Heterocyclyl, optionally substituted -(O)C 4~12 Aryl, optionally substituted -(O)C 1~6 Alkyl C 5~12 Aryl, optionally substituted -(O)C 1~12 Heteroaryl and optionally substituted -(O)C 1~6 Alkyl C 1~12 heteroaryl, the dashed bond is present or absent, X is CH or O, and Z is CHR a , N.R. a , or O, and R a is hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amide, optionally substituted N-amide, optionally substituted ester, optionally substituted -(O)C 1~6 Alkyl, optionally substituted -(O)C 1~6 Alkenyl, optionally substituted -(O)C 1~6 Alkynyl, optionally substituted -(O)C 4~12 Cycloalkyl, optionally substituted -(O)C 1~6 Alkyl C 4~12Cycloalkyl, optionally substituted -(O)C 4~12 Heterocyclyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Heterocyclyl, optionally substituted -(O)C 4~12 Aryl, optionally substituted -(O)C 1~6 Alkyl C 5~12 Aryl, optionally substituted -(O)C 1~12 Heteroaryl and optionally substituted -(O)C 1~6 Alkyl C 1~12 Selected from heteroaryls, which improve digestive health.

[0010] In some embodiments, the compound has the structure of Formula II.

[0011] [ka]

[0012] In some embodiments, R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted -(O)C 1~6 Alkyl, optionally substituted -(O)C 1~6 Alkenyl, optionally substituted -(O)C 1~6 Alkynyl, optionally substituted -(O)C 4~12 Cycloalkyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Cycloalkyl, optionally substituted -(O)C 4~12 Heterocyclyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Heterocyclyl, optionally substituted -(O)C 4~12 Aryl, optionally substituted -(O)C1~6 Alkyl C 5~12 Aryl, optionally substituted -(O)C 1~12 Heteroaryl and optionally substituted -(O)C 1~6 Alkyl C 1~12 heteroaryl, the dashed bond may be present or absent, and Z is selected from CHR a , N.R. a , or O, and R a is hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amide, optionally substituted N-amide, optionally substituted ester, optionally substituted -(O)C 1~6 Alkyl, optionally substituted -(O)C 1~6 Alkenyl, optionally substituted -(O)C 1~6 Alkynyl, optionally substituted -(O)C 4~12 Cycloalkyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Cycloalkyl, optionally substituted -(O)C 4~12 Heterocyclyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Heterocyclyl, optionally substituted -(O)C 4~12 Aryl, optionally substituted -(O)C 1~6 Alkyl C 5~12 Aryl, optionally substituted -(O)C 1~12 Heteroaryl and optionally substituted -(O)C 1~6 Alkyl C 1~12 heteroaryl.

[0013] In some embodiments, the extract is an ethanol extract of a member of the genus Allium, Amoracia, Chenopodium, Spinacia, Fagopyrum, Annona, Jatropha, Hibiscus, Piper, Eragrostis, Zea, Nelumbo, Cannabis, Ziziphus, Zanthoxylum, Ipomea, Capsicum, Lycium, Solanum, or Tribulus.

[0014] In some embodiments, the composition is formulated as a dietary supplement, a food ingredient or additive, a medical food, a nutraceutical, or a pharmaceutical composition.

[0015] In some embodiments, the compound of Formula (I) or Formula (II) is selected from the group consisting of N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and 5-hydroxyferuloyltyramine, or a pharmaceutically acceptable salt, solvate, or combination of the foregoing.

[0016] In some embodiments, the compound of Formula (I) or Formula (II) is (E)-3-(3,4-dihydroxyphenyl)-N-(4-ethoxyphenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-methoxyethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-(methylsulfonyl)ethoxy)phenethyl)acrylamide, (E)-2-(4-(2-(3-(3,4-dihydroxyphenyl)acrylamido)ethyl)phenoxy)acetic acid, ethyl ... -(4-(2-(3-(3,4-dihydroxyphenyl)acrylamido)ethyl)phenoxy)acetate, (E)-N-(4-(cyclopropylmethoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(3,3,3-trifluoropropoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-4-yl)methoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydro (E)-N-(4-(4-fluorobenzyl)oxy)phenethyl)acrylamide, (E)-N-(4-(cyanomethoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-3-ylmethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-2-ylmethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-(dimethylamino) (E)-3-(3,4-dihydroxyphenyl)-N-(4-isobutoxyphenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-4-ylmethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((4-methoxybenzyl)oxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(oxetan-3-ylmethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-2-yl)methoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydrofuran-2-yl)methoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(thiophen-2-yloxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(3,3-dimethylbutoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-hydroxyethoxy)phenethyl)acrylamide, (E)-N-(4-((1H-tetrazol-5-yl)methoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((1-methylpyrrolidin-2-yl)methoxy)phenethyl)acrylamide, (E)-2-hydroxy-5-(3-((4-hydroxyphenethyl)amino)-3-oxoprop-1-en-1-yl)phenyl hydrogen carbonate, (E)-3-(4-hydroxy-3-(pyridin-4-yloxy)phenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-3-(4-hydroxy-3-isobutoxyphenyl)-N-(4-hydroxyphenethyl)acryl acrylamide, (E)-3-(3-(4-fluorophenoxy)-4-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-3-(3-(cyanomethoxy)-4-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-2-(2-hydroxy-4-(3-((4-hydroxyphenethyl)amino)-3-oxoprop-1-en-1-yl)phenoxy)acetic acid, (E)-3-(3-hydroxy-4-(pyridin-4-ylmethoxy)phenyl)-N-(4-hydroxyphenyl)- (E)-3-(4-((4-fluorobenzyl)oxy)-3-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-3-(3-hydroxy-4-isobutoxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-3-(4-(cyanomethoxy)-3-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-N-(3-(3,4-dihydroxyphenyl)acryloyl)-N-(4-hydroxyphenethyl)acrylamide (E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)glycine, (E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)-N-(pyridin-4-ylmethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)-N-isobutylacrylamide, (E)-N-(cyanomethyl)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, 3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)propanamide, 3-(3,4-dihydroxyphenyl)-N-(4-(methylsulfonamido)phenethyl)propanamide, or a pharmaceutical salt, solvate, or combination thereof.

[0017] In some embodiments, the composition of Formula (I) or Formula (II) is in unit dosage form and is configured for administration at 0.1 to 100 mg / kg of subject body weight per dose.

[0018] In some embodiments, administering a compound of Formula (I) or Formula (II) increases HNF4α expression.

[0019] In some embodiments, administering a compound of Formula (I) or Formula (II) reverses the loss of Paneth cells that results from a high-fat diet.

[0020] In some embodiments, a method of treating or preventing a disease or disorder in a subject comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof;

[0021] [ka]

[0022] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted -(O)C 1~6 Alkyl, optionally substituted -(O)C 1~6 Alkenyl, optionally substituted -(O)C 1~6 Alkynyl, optionally substituted -(O)C 4~12Cycloalkyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Cycloalkyl, optionally substituted -(O)C 4~12 Heterocyclyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Heterocyclyl, optionally substituted -(O)C 4~12 Aryl, optionally substituted -(O)C 1~6 Alkyl C 5~12 Aryl, optionally substituted -(O)C 1~12 Heteroaryl and optionally substituted -(O)C 1~6 Alkyl C 1~12 heteroaryl, the dashed bond is present or absent, X is CH or O, and Z is CHR a , N.R. a , or O, and R a is hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amide, optionally substituted N-amide, optionally substituted ester, optionally substituted -(O)C 1~6 Alkyl, optionally substituted -(O)C 1~6 Alkenyl, optionally substituted -(O)C 1~6 Alkynyl, optionally substituted -(O)C 4~12 Cycloalkyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Cycloalkyl, optionally substituted -(O)C 4~12 Heterocyclyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Heterocyclyl, optionally substituted -(O)C 4~12 Aryl, optionally substituted -(O)C 1~6 Alkyl C 5~12 Aryl, optionally substituted -(O)C 1~12 Heteroaryl and optionally substituted -(O)C 1~6 Alkyl C 1~12 heteroaryl), The disease or disorder is related to the gut method.

[0023] In some embodiments, administering a compound of Formula (I) induces a significant increase in HNF4α.

[0024] In some embodiments, administering a compound of Formula (I) increases intestinal villi.

[0025] In some embodiments, administering a compound of Formula (I) increases the formation of Paneth cells.

[0026] In some embodiments, the liver- or intestinal-related disease or disorder is inflammation.

[0027] In some embodiments, the gut-related disease or disorder is a condition associated with an allergic reaction.

[0028] Features and advantages of the compositions and methods described herein will become apparent from the following description taken in conjunction with the accompanying drawings. These drawings illustrate certain aspects of the compositions and methods described herein and therefore should not be considered limiting. In the drawings, like reference numbers or symbols typically indicate like components unless the context dictates otherwise. The drawings are not drawn to scale. [Brief explanation of the drawings]

[0029] [Figure 1] Figure 1 illustrates the dose-response analysis of N-trans-caffeoyltyramine, N-trans-feruloyltyramine, and p-coumaroyltyramine in an assay measuring insulin promoter activity. Dimethyl sulfoxide (DMSO) and alverine (20 μM) were used as negative and positive controls, respectively. [Figure 2]Figure 1 illustrates the effects of N-trans-caffeoyltyramine, N-trans-feruloyltyramine, and p-coumaroyltyramine on HNF4α mRNA levels as determined by quantitative PCR. DMSO and alverine (20 μM) were used as negative and positive controls, respectively. [Figure 3]Figure 3 shows Tribulus terrestris seeds (1), Cannabis sativa (hemp) seed husks (2), Annona species (atemoya) seeds (3), Annona muricata (soursop) seeds (4), A. cherimola (cherimoya) leaves (5), Zea mays stems (6), Tribulus terrestris (Goat Head) seeds (7), A. cherimola hardwood (bark and pith) (8), Solanum lycopersicum pomace (9), S. tuberosum (yellow potato) skins (10), and Piper nigrum (11). nigrum (black pepper) fruit (11), S. tuberosum (purple potato) skin (12), S. tuberosum (red potato) skin (13), S. lycopersicum pomace (14), S. lycopersicum extruded pomace (15), A. muricata (soursop) leaf (16), Allium sativum (garlic) bulb (17), S. tuberosum (purple potato) skin (18), A. montana (A. montana (Soursop) leaves (19), Z. mycena (Z. mycena) leaves (20), S. tuberosum (purple potato) shoots (21), A. cherimola (cherimoya) seeds (22), Allium fistulosum (Allium fistulosum (green onion) whole plant (23), S. tuberosum (white potato) skin (24), A. cherimola (cherimoya) raw wood (25), Cannabis sativa (maize) leaf (26), S. tuberosum (white potato) skin (27), S. lycopersicum seed (28), S. lycopersicum (beefsteak) whole fruit (29), A. muricata (soursop (Guarabana)) immature fruit skin (30), A. muricata (soursop) fresh ripe fruit (31), A. squamosa (Sugar Apple) whole fruit (32), Capsicum annuum (Chilean serrano) fruit (33), S.S. tuberosum (Russet potato) peel (34), Lycium barbarum (goji berry / wolfberry) fruit (35), S. tuberosum (purple potato) core (36), Chenopodium quinoa (quinoa) seed (37), Ipomoea batatas (sweet potato) whole tuber (38), Ipomoea batatas (sweet potato) peel (39), Armoracia rusticana (horseradish) root (40), S. tuberosum (Colorado potato) peel (41), Fagopyrum esculentum (buckwheat) husk (42), Capsicum frutescens The figures illustrate the amounts of N-trans-caffeoyltyramine, N-trans-feruloyltyramine, and p-coumaroyltyramine present in ethanol extracts (% of extract, w / w) from various sources, including S. frutescens (spicy pepper) fruit (43), S. tuberosum (purple potato) core (44), C. annuum (Thai chili) stem and leaf (45), A. murikata (soursop) fresh unripe fruit (46), S. tuberosum (yellow potato) core (47), and Eragrostis tef (teff) seed (48). [Figure 4] FIG. 4 illustrates that HNF4α is increased in the intestine of DIO mice treated with NCT. [Figure 5] FIG. 5 illustrates that Paneth cells are increased in the intestine of DIO mice treated with NCT. DETAILED DESCRIPTION OF THE INVENTION

[0030] Tyramine-containing hydroxycinnamic acid amides and extracts containing them, isolated from natural sources, have now been shown to increase or improve HNF4α expression / activity. Because reduced expression of HNF4α in the intestinal epithelial layer has been shown to be associated with IBD pathogenesis and other chronic conditions associated with gastrointestinal inflammation, these natural compounds and extracts can be used to restore digestive health in IBD and other chronic gastrointestinal conditions. Advantageously, the compounds and extracts of the present disclosure have several potential advantages, including high patient acceptance, relative safety, low cost, and use as a complementary approach to traditional Western medical approaches.

[0031] The tyramine-containing hydroxycinnamic acid amides of the present disclosure are analogs of lead compounds identified in traditional screening assays for drugs that modulate known signaling pathways. They exhibit dose-responsive HNF4α activity and elevate HNF4α mRNA levels, as initially determined in T6PNE-engineered pancreatic cells. Without wishing to be bound by theory, it is believed that the tyramine-containing hydroxycinnamic acid amides of the present disclosure elevate HNF4α activity and downregulate HNF4α activity as a result of their higher affinity for the HNF4α binding site than the natural ligand, palmitic acid. Thus, by elevating HNF4α activity, the compounds of the present disclosure can be used to improve digestive function and thereby address the underlying etiology of gastrointestinal disorders such as IBD, UC, and CD. Use of the compositions of the present disclosure improves and promotes health and well-being.

[0032] composition In some aspects, the disclosure provided herein provides plant-derived aromatic metabolites having one or more acidic hydroxyl groups attached to an aromatic arene, and their use in modulating metabolism. In one embodiment, the plant-derived aromatic metabolite is a structural analog of Compound 1.

[0033] [ka]

[0034] In particular, the disclosure encompasses compounds of formula (I), or an isomer, salt, homodimer, heterodimer, or conjugate thereof.

[0035] [ka]

[0036] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted -(O)C 1~6 Alkyl, optionally substituted -(O)C 1~6 Alkenyl, optionally substituted -(O)C 1~6 Alkynyl, optionally substituted -(O)C 4~12 Cycloalkyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Cycloalkyl, optionally substituted -(O)C 4~12 Heterocyclyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Heterocyclyl, optionally substituted -(O)C 4~12 Aryl, optionally substituted -(O)C 1~6 Alkyl C 5~12 Aryl, optionally substituted -(O)C 1~12 Heteroaryl and optionally substituted -(O)C 1~6 Alkyl C 1~12 heteroaryl.

[0037] In some embodiments, R 1 , R 2 , R 3 , and R 8 are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted -(O)C 1~6 Alkyl, optionally substituted -(O)C 1~6 Alkenyl, optionally substituted -(O)C 1~6 Alkynyl, optionally substituted -(O)C 4~12 Cycloalkyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Cycloalkyl, optionally substituted -(O)C 4~12 Heterocyclyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Heterocyclyl, optionally substituted -(O)C 4~12 Aryl, optionally substituted -(O)C 1~6 Alkyl C 5~12 Aryl, optionally substituted -(O)C 1~12 Heteroaryl and optionally substituted -(O)C 1~6 Alkyl C 1~12 heteroaryl; R 4 , R 5 , R 6 , R 7 , and R 9 are each independently hydrogen, deuterium, hydroxyl, or halogen.

[0038] In some embodiments, R 1 , R 2 , and R 8 are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted -(O)C 1~6 Alkyl, optionally substituted -(O)C 1~6Alkenyl, optionally substituted -(O)C 1~6 Alkynyl, optionally substituted -(O)C 4~12 Cycloalkyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Cycloalkyl, optionally substituted -(O)C 4~12 Heterocyclyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Heterocyclyl, optionally substituted -(O)C 4~12 Aryl, optionally substituted -(O)C 1~6 Alkyl C 5~12 Aryl, optionally substituted -(O)C 1~12 Heteroaryl and optionally substituted -(O)C 1~6 Alkyl C 1~12 heteroaryl; R 3 , R 4 , R 5 , R 6 , R 7 , and R 9 are each independently hydrogen, deuterium, hydroxyl, or halogen.

[0039] In some embodiments, the dashed bond may or may not be present.

[0040] In some embodiments, X is CH2 or O.

[0041] In some embodiments, Z is CHR a , N.R. a , or O.

[0042] In some embodiments, R a is hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amide, optionally substituted N-amide, optionally substituted ester, optionally substituted -(O)C 1~6 Alkyl, optionally substituted -(O)C 1~6 Alkenyl, optionally substituted -(O)C1~6 Alkynyl, optionally substituted -(O)C 4~12 Cycloalkyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Cycloalkyl, optionally substituted -(O)C 4~12 Heterocyclyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Heterocyclyl, optionally substituted -(O)C 4~12 Aryl, optionally substituted -(O)C 1~6 Alkyl C 5~12 Aryl, optionally substituted -(O)C 1~12 Heteroaryl and optionally substituted -(O)C 1~6 Alkyl C 1~12 heteroaryl.

[0043] In some embodiments, the compound of formula (I) is provided as a pharmaceutically acceptable salt or solvate thereof.

[0044] In some embodiments, the compound of formula (I) is (E)-3-(3,4-dihydroxyphenyl)-N-(4-ethoxyphenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-methoxyethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-(methylsulfonyl)ethoxy)phenethyl)acrylamide, (E)-2-(4-(2-(3-(3,4-dihydroxyphenyl)acrylamido)ethyl)phenoxy)acetic acid, ethyl (E)-2-(4-( 2-(3-(3,4-dihydroxyphenyl)acrylamido)ethyl)phenoxy)acetate, (E)-N-(4-(cyclopropylmethoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(3,3,3-trifluoropropoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-4-yl)methoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-4-yl)methoxy)phenethyl)acrylamide (E)-N-(4-(cyanomethoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-3-ylmethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-2-ylmethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-(dimethylamino)ethoxy)ethyl)acrylamide (E)-3-(3,4-dihydroxyphenyl)-N-(4-isobutoxyphenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-4-ylmethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((4-methoxybenzyl)oxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(oxetan-3-ylmethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-2-yl)methoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydrofuran-2-yl)methoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(thiophen-2-yloxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(3,3-dimethylbutoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-hydroxyethoxy)phenethyl)acrylamide, (E)-N-(4-((1H-tetrazol-5-yl)methoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((1-methylpyrrolidin-2-yl)methoxy)phenethyl)acrylamide, (E)-2-hydroxy-5-(3-((4-hydroxyphenethyl)amino)-3-oxoprop-1-en-1-yl)phenyl hydrogen carbonate, (E)-3-(4-hydroxy-3-(pyridin-4-yloxy)phenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-3-(4-hydroxy-3-isobutoxyphenyl)-N-(4-hydroxyphenethyl)acryl acrylamide, (E)-3-(3-(4-fluorophenoxy)-4-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-3-(3-(cyanomethoxy)-4-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-2-(2-hydroxy-4-(3-((4-hydroxyphenethyl)amino)-3-oxoprop-1-en-1-yl)phenoxy)acetic acid, (E)-3-(3-hydroxy-4-(pyridin-4-ylmethoxy)phenyl)-N-(4-hydroxyphenyl)- (E)-3-(4-((4-fluorobenzyl)oxy)-3-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-3-(3-hydroxy-4-isobutoxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-3-(4-(cyanomethoxy)-3-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-N-(3-(3,4-dihydroxyphenyl)acryloyl)-N-(4-hydroxyphenethyl)acrylamide (E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)glycine, (E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)-N-(pyridin-4-ylmethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)-N-isobutylacrylamide, (E)-N-(cyanomethyl)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, 3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)propanamide, 3-(3,4-dihydroxyphenyl)-N-(4-(methylsulfonamido)phenethyl)propanamide, or pharmaceutical salts, solvates, and combinations thereof.

[0045] In some embodiments, the disclosure encompasses compounds of formula (II).

[0046] [ka]

[0047] In some embodiments, R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted -(O)C 1~6 Alkyl, optionally substituted -(O)C 1~6 Alkenyl, optionally substituted -(O)C 1~6 Alkynyl, optionally substituted -(O)C 4~12 Cycloalkyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Cycloalkyl, optionally substituted -(O)C 4~12 Heterocyclyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Heterocyclyl, optionally substituted -(O)C 4~12 Aryl, optionally substituted -(O)C 1~6 Alkyl C 5~12 Aryl, optionally substituted -(O)C 1~12 Heteroaryl and optionally substituted -(O)C 1~6 Alkyl C 1~12 heteroaryl.

[0048] In some embodiments, the dashed bond may or may not be present.

[0049] In some embodiments, Z is CHR a , N.R. a , or O.

[0050] In some embodiments, R a is hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amide, optionally substituted N-amide, optionally substituted ester, optionally substituted -(O)C 1~6 Alkyl, optionally substituted -(O)C 1~6 Alkenyl, optionally substituted -(O)C 1~6 Alkynyl, optionally substituted -(O)C 4~12 Cycloalkyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Cycloalkyl, optionally substituted -(O)C 4~12 Heterocyclyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Heterocyclyl, optionally substituted -(O)C 4~12 Aryl, optionally substituted -(O)C 1~6 Alkyl C 5~12 Aryl, optionally substituted -(O)C 1~12 Heteroaryl and optionally substituted -(O)C 1~6 Alkyl C 1~12 heteroaryl.

[0051] In some embodiments, the compound of formula (II) is (E)-3-(3,4-dihydroxyphenyl)-N-(4-ethoxyphenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-methoxyethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-(methylsulfonyl)ethoxy)phenethyl)acrylamide, (E)-2-(4-(2-(3-(3,4-dihydroxyphenyl)acrylamido)ethyl)phenoxy)acetic acid, ethyl (E)-2-(4- (2-(3-(3,4-dihydroxyphenyl)acrylamido)ethyl)phenoxy)acetate, (E)-N-(4-(cyclopropylmethoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(3,3,3-trifluoropropoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-4-yl)methoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-4-yl)methoxy)phenethyl)acrylamide (E)-N-(4-((4-fluorobenzyl)oxy)phenethyl)acrylamide, (E)-N-(4-(cyanomethoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-3-ylmethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-2-ylmethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-(dimethylamino)ethoxy)ethyl)acrylamide (E)-3-(3,4-dihydroxyphenyl)-N-(4-isobutoxyphenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-4-ylmethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((4-methoxybenzyl)oxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(oxetan-3-ylmethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-2-yl)methoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydrofuran-2-yl)methoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(thiophen-2-yloxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(3,3-dimethylbutoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-hydroxyethoxy)phenethyl)acrylamide, (E)-N-(4-((1H-tetrazol-5-yl)methoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((1-methylpyrrolidin-2-yl)methoxy)phenethyl)acrylamide, (E)-2-hydroxy-5-(3-((4-hydroxyphenethyl)amino)-3-oxoprop-1-en-1-yl)phenyl hydrogen carbonate, (E)-3-(4-hydroxy-3-(pyridin-4-yloxy)phenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-3-(4-hydroxy-3-isobutoxyphenyl)-N-(4-hydroxyphenethyl)acryl acrylamide, (E)-3-(3-(4-fluorophenoxy)-4-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-3-(3-(cyanomethoxy)-4-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-2-(2-hydroxy-4-(3-((4-hydroxyphenethyl)amino)-3-oxoprop-1-en-1-yl)phenoxy)acetic acid, (E)-3-(3-hydroxy-4-(pyridin-4-ylmethoxy)phenyl)-N-(4-hydroxyphenyl)- (E)-3-(4-((4-fluorobenzyl)oxy)-3-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-3-(3-hydroxy-4-isobutoxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-3-(4-(cyanomethoxy)-3-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-N-(3-(3,4-dihydroxyphenyl)acryloyl)-N-(4-hydroxyphenethyl)acrylamide (E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)glycine, (E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)-N-(pyridin-4-ylmethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)-N-isobutylacrylamide, (E)-N-(cyanomethyl)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, 3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)propanamide, 3-(3,4-dihydroxyphenyl)-N-(4-(methylsulfonamido)phenethyl)propanamide, or pharmaceutical salts, solvates, and combinations thereof.

[0052] In some embodiments, the compound of formula (II) is provided as a pharmaceutically acceptable salt or solvate thereof.

[0053] In some embodiments, the disclosure encompasses compounds of formula (III).

[0054] [ka]

[0055] In some embodiments, R 3 and R 4 are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted -(O)C 1~6 Alkyl, optionally substituted -(O)C 1~6 Alkenyl, optionally substituted -(O)C 1~6 Alkynyl, optionally substituted -(O)C 4~12 Cycloalkyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Cycloalkyl, optionally substituted -(O)C 4~12 Heterocyclyl, optionally substituted -(O)C 1~6 Alkyl C 2~12 Heterocyclyl, optionally substituted -(O)C 5~12 Aryl, optionally substituted -(O)C 1~6 Alkyl C 5~12 Aryl, optionally substituted -(O)C 1~12 Heteroaryl and optionally substituted -(O)C 1~6 Alkyl C 1~12 heteroaryl.

[0056] In some embodiments, each independently selected dashed bond is either present or absent.

[0057] In some embodiments, Z is CHR a , N.R. a , or O.

[0058] In some embodiments, R a is hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amide, optionally substituted N-amide, optionally substituted ester, optionally substituted -(O)C 1~6 Alkyl, optionally substituted -(O)C 1~6 Alkenyl, optionally substituted -(O)C 1~6 Alkynyl, optionally substituted -(O)C 4~12 Cycloalkyl, optionally substituted -(O)C 4~12 Heterocyclyl, optionally substituted -(O)C 4~12 Cycloalkyl, optionally substituted -(O)C 1~6 Alkyl C 5~12 Aryl, optionally substituted -(O)C 1~6 Alkyl C 5~12 heteroaryl.

[0059] In some embodiments, Q a , Q b , Q c , Q d each independently represents a bond, CHR a , N.R. a , C═O, and —O—.

[0060] In some embodiments, R a is hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amide, optionally substituted N-amide, optionally substituted ester, optionally substituted -(O)C 1~6 Alkyl, optionally substituted -(O)C1~6 Alkenyl, optionally substituted -(O)C 1~6 Alkynyl, optionally substituted -(O)C 4~12 Cycloalkyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Cycloalkyl, optionally substituted -(O)C 4~12 Heterocyclyl, optionally substituted -(O)C 1~6 Alkyl C 4~12 Heterocyclyl, optionally substituted -(O)C 4~12 Aryl, optionally substituted -(O)C 1~6 Alkyl C 5~12 Aryl, optionally substituted -(O)C 1~12 Heteroaryl and optionally substituted -(O)C 1~6 Alkyl C 1~12 heteroaryl.

[0061] In some embodiments, Q c , Q d In some embodiments, Q d does not exist.

[0062] In some embodiments, n is 1, 2, 3, or 4.

[0063] In some embodiments, the compound of formula (II) is provided as a pharmaceutically acceptable salt or solvate thereof.

[0064] "Isomers" refers inter alia to optical isomers (e.g., essentially pure enantiomers, essentially pure diastereomers, and mixtures thereof), as well as conformational isomers (i.e., isomers that differ only in the angle of at least one chemical bond), positional isomers (especially tautomers), and geometric isomers (e.g., cis-trans isomers).

[0065] In certain embodiments, the compound of formula (I) or formula (II) is

[0066] [ka]

[0067] is selected from.

[0068] A salt of a compound of the present disclosure refers to a compound that possesses the desired pharmacological activity of the parent compound and is formed with (1) an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an acid such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, or the like. These include (1) acid addition salts formed with organic acids such as benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, 4-toluenesulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced.

[0069] As known in the art, a homodimer is a molecule consisting of two identical tyramine-containing hydroxycinnamic acid amide subunits. In comparison, a heterodimer is a molecule consisting of two different tyramine-containing hydroxycinnamic acid amide subunits. Examples of homodimers of the present disclosure include, but are not limited to, cross-linked N-trans-feruloyltyramine dimers, cross-linked N-trans-caffeoyltyramine dimers, and cross-linked p-coumaroyltyramine dimers. See, for example, King and Calhoun (2005) Phytochemistry 66(20):2468-73, which teaches the isolation of cross-linked N-trans-feruloyltyramine dimers from potato scab lesions.

[0070] Conjugates of tyramine-containing hydroxycinnamic acid amide monomers with other compounds, such as lignanamides. Examples of conjugates include, but are not limited to, cannabidiin A, cannabidiin B, cannabidiin C, cannabidiin D, cannabidiin E, cannabidiin F, and glossamide.

[0071] Whenever a group is described as "optionally substituted," the group can be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as "unsubstituted or substituted," if substituted, the substituents can be selected from one or more of the indicated substituents. When no substituents are specified, the specified "optionally substituted" or "substituted" group can be any of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thio It means that each may be independently substituted with one or more groups independently selected from carbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanate, thiocyanate, isothiocyanate, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, monosubstituted amino groups, disubstituted amino groups, and protected derivatives thereof.

[0072] For groups herein, the parenthesized subscripts below further define the group as follows: n) defines the exact number (n) of carbon atoms in the group. For example, "C1-C6-alkyl" refers to those alkyl groups having from 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6, or any range derivable therein (e.g., 3 to 6 carbon atoms)).

[0073] In addition to isomers, salts, homodimers, heterodimers, and conjugates, the tyramine-containing hydroxycinnamic acid amide may also be glycosylated. Glycosylated tyramine-containing hydroxycinnamic acid amides can be produced by transglucosylating the tyramine-containing hydroxycinnamic acid amide to add glucose units, e.g., 1, 2, 3, 4, 5, or more than 5 glucose units, to the tyramine-containing hydroxycinnamic acid amide. Transglucosylation can be carried out with any suitable enzyme, including, but not limited to, pullulanase and isomaltase (Lobov et al. (1991) Agric. Biol. Chem. 55:2959-2965), -galactosidase (Kitahata et al. (1989) Agric. Biol. Chem. 53:2923-2928), dextrin saccharase (Yamamoto et al. (1994) Biosci. Biotech. Biochem. 58:1657-1661), or cyclodextrin glucanotransferase, with pullulan, maltose, lactose, partially hydrolyzed starch, and maltodextrin as donors.

[0074] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain, including fully saturated (no double or triple bonds) hydrocarbon groups. The alkyl group can have 1 to 20 carbon atoms. (Whenever an alkyl group appears herein, a numerical range such as "1 to 20" refers to each integer within the given range; for example, "1 to 20 carbon atoms" means the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 20 carbon atoms; however, this definition also encompasses the occurrence of the term "alkyl" even when no numerical range is specified.) The alkyl group can also be a medium-sized alkyl having 1 to 10 carbon atoms. The alkyl group can also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of a compound can be designated as "C1-C4 alkyl" or similar designation. By way of example only, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted.

[0075] The terms "halogen atom" or "halogen," as used herein, refer to any one of the radioactive stable atoms in column 7 of the periodic table of the elements, such as chloro (Cl), fluoro (F), bromo (Br), and iodo (I) groups.

[0076] In any of the groups described herein, an available hydrogen can be replaced with alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, alkoxyalkoxy, alkoxycarbonyl, acyl, halo, nitro, aryloxycarbonyl, cyano, carboxy, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, or heterocyclyl.

[0077] An undefined valency on an atom of a structure depicted herein implicitly represents a hydrogen atom bonded to the atom.

[0078] As used herein, "alkenyl" refers to an alkyl group, as defined herein, containing one or more double bonds in the straight or branched hydrocarbon chain. An alkenyl group can be unsubstituted or substituted.

[0079] As used herein, "alkynyl" refers to an alkyl group, as defined herein, containing one or more triple bonds in the straight or branched hydrocarbon chain. An alkynyl group can be unsubstituted or substituted.

[0080] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring system that is fully saturated (no double or triple bonds). When composed of more than one ring, the rings can be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring, or 3 to 8 atoms in the ring. Cycloalkyl groups can be unsubstituted or substituted. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0081] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including, for example, fused, bridged, or spiro ring systems in which two carbocyclic rings share a chemical bond, e.g., one or more aryl rings with one or more aryl or non-aryl rings) having a completely delocalized pi-electron system throughout at least one of the rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be any of C6 to C6. 14 Aryl groups, C6-C 10 The aryl group may be a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0082] As used herein, "heterocyclyl" refers to a monocyclic or polycyclic ring system containing at least one heteroatom (e.g., O, N, S). Such systems can be unsaturated, contain some unsaturation, or contain some aromatic moieties or all aromatic. Heterocyclyl groups can contain from 3 to 30 atoms. Heterocyclyl groups can be unsubstituted or substituted.

[0083] In certain embodiments, R 1 is present and represents a hydroxy group at the para position, and R 2 is a hydroxy group or a lower alkoxy group at the meta position. In certain embodiments, the tyramine-containing hydroxycinnamic acid amide having the structure of formula (I) is in the trans configuration.

[0084] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system having at least one ring with a completely delocalized π-electron system) containing one or more heteroatoms, i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur, and at least one aromatic ring. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, a heteroaryl group can contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Furthermore, the term "heteroaryl" includes fused ring systems, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, where two rings share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl groups can be substituted or unsubstituted.

[0085] The term "amino," as used herein, refers to the group --NH.sub.2.

[0086] As used herein, the term "hydroxy" refers to an --OH group.

[0087] A "cyano" group refers to a "-CN" group.

[0088] A "carbonyl" group refers to a C=O group.

[0089] A "C-amide" group is a group consisting of -C(=O)N(RA R B ) group, and R A and R B may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. C-amides may be substituted or unsubstituted.

[0090] The "N-amide" group is defined as "RC(=O)N(R A )-" group, and R and R A may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. N-amides may be substituted or unsubstituted.

[0091] The "urea group" is "-N(R A R B )-C(=O)-N(R A R B )-" group, R A and R B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. The urea group can be substituted or unsubstituted.

[0092] The term "pharmaceutically acceptable salt," as used herein, is a broad term and is given its ordinary and common meaning to those skilled in the art (not limited to any special or modified meaning), and refers, without limitation, to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting the compound with inorganic acids such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as an aliphatic or aromatic carboxylic or sulfonic acid, for example, formic acid, acetic acid (AcOH), propionic acid, glycolic acid, pyruvic acid, malonic acid, maleic acid, fumaric acid, trifluoroacetic acid (TFA), benzoic acid, cinnamic acid, mandelic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, for example, an alkali metal salt such as an ammonium salt, lithium salt, sodium salt, or potassium salt; an alkaline earth metal salt such as a calcium salt, magnesium salt, or aluminum salt; a salt with an organic base such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine; a salt with an amino acid such as arginine and lysine; or a salt with an inorganic base such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.

[0093] For any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center in that case may independently be in the R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, or a stereoisomeric mixture, including all diastereomeric and enantiomeric forms. Additionally, for any compound described herein having one or more double bonds that produce conformational isomers that can be defined as E or Z, it is understood that each double bond may independently be E or Z, or a mixture thereof. Stereoisomers may be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns.

[0094] Likewise, for any compound described, it will be understood that all tautomeric forms are also intended to be included.

[0095] It is understood that the compounds described herein can be isotopically labeled or labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Substitution with isotopes such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood as being present in the compound. At any position in a compound where a hydrogen atom can be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus, reference herein to a compound encompasses all possible isotopic forms unless the context clearly dictates otherwise.

[0096] It is understood that the compounds described herein can be isotopically labeled or labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Substitution with isotopes such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood as being present in the compound. At any position in a compound where a hydrogen atom can be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus, reference herein to a compound encompasses all possible isotopic forms unless the context clearly dictates otherwise.

[0097] It is understood that the methods and formulations described herein include the use of crystalline forms, amorphous phases, and / or pharmaceutically acceptable salts, solvates, hydrates, and conformers of the compounds of some embodiments, as well as metabolites and active metabolites of these compounds that have the same type of activity. Conformers are structures that are conformers. Conformers are events of molecules with the same structural formula, but with different configurations (conformers) of atoms about a rotatable bond. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In other embodiments, the compounds described herein exist in unsolvated forms. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and can be formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds described herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods described herein. Other forms in which the compounds of some embodiments may be provided include amorphous, micronized, and nanoparticulate forms.

[0098] Similarly, it will be understood that the compounds described herein, such as the compounds of some embodiments, include the compounds in any of the forms described herein (e.g., pharmaceutically acceptable salts, prodrugs, crystalline forms, amorphous forms, solvated forms, enantiomeric forms, tautomeric forms, etc.).

[0099] Source of active compounds The compounds of the present disclosure can be obtained from any suitable plant species and / or plant source known to have the compound of formula (I). Preferably, the compound is provided as an extract containing the compound or as a substantially pure compound.

[0100] "Extract" refers to a composition containing a compound of Formula (I), which is separated from other undesired substances present in the natural source material from which the extract is obtained. In some embodiments, the natural source material is a plant. Plant extracts can be obtained from any plant tissue, including whole plants, plant parts such as shoot vegetative organs / structures (e.g., leaves, stems, and tubers), roots, flowers, and floral organs / structures (e.g., bracts, sepals, petals, stamens, carpels, anthers, and ovules), seeds (including embryos, endosperm, and seed coats), or fruits (mature ovaries), plant tissues (e.g., vascular tissue, ground tissue, etc.), cells (e.g., guard cells, egg cells, etc.), or exudates, as well as their progeny and cultures or cell lines. Preferably, the extract contains compounds found to be Generally Regarded as Safe (GRAS) for human consumption. Thus, in certain embodiments, the extract is derived from an edible source. In this regard, the extract is an edible extract.

[0101] Extracts can be prepared by freezing, grinding, maceration, crushing, fermenting, percolation, decoction, solvent extraction (e.g., partitioning) or precipitation of the source material of interest, treatment with activated carbon, evaporation, filtration, and / or chromatographic fractionation. In this regard, an "extract" of the present disclosure can be, but is not limited to, crude, fractionated, subfractionated, separated, isolated, enriched, or purified. The term "crude" refers to a compound or molecule that has not been completely separated from the components of the original composition in which it is present. In embodiments involving fractionation or subfractionation, the molecules of the crude extract can be subjected to partial separation to produce a crude product containing fewer other substances. In some embodiments, a compound is isolated. The term "isolated" means that the compound or molecule is substantially enriched or purified relative to the complex cellular environment in which it occurs in nature, such as in a crude extract. When isolated molecules are enriched or purified, the absolute level of purity is not critical, and one of skill in the art can easily determine an appropriate level of purity by use of the material. In some situations, an isolated molecule will form part of a composition (e.g., a somewhat crude extract containing many other substances), which may contain, for example, other components. In other situations, an isolated molecule can be purified to essential homogeneity, as determined spectrophotometrically, for example, by NMR or chromatography (e.g., LC-MS).

[0102] Suitable solvents for preparing the extract include, in any proportion, n-pentane, hexane, butane, chloroform, dichloromethane, diethyl ether, acetonitrile, water, butanol, isopropanol, ethanol, methanol, glacial acetic acid, acetone, butanone, pentanone, norflurane (HFA134a), ethyl acetate, dimethyl sulfoxide, heptafluoropropane (HFA227), and subcritical or supercritical fluids such as liquid carbon dioxide and water, or combinations thereof. When using solvents such as those listed above, the resulting extract typically contains nonspecific, lipid-soluble substances. This can be removed by various processes, including "winterization," which involves cooling to a certain temperature, typically -20°C, followed by filtration or centrifugation to remove the waxy ballast, extraction with subcritical or supercritical carbon dioxide or a nonpolar solvent (e.g., hexane), and distillation.

[0103] Extracts enriched for the compounds of the present disclosure are ideally obtained by chromatographic fractionation. Chromatographic fractionation typically involves column chromatography and can be based on molecular size, charge, solubility, and / or polarity. Depending on the type of chromatographic method, column chromatography can be performed using matrix materials such as dextran, agarose, polyacrylamide, silica, C18, C8, polyvinylpyrrolidone, polystyrene, Celite, and phenyl-hexyl, and can include solvents such as dimethyl sulfoxide, pyridine, water, dimethylformamide, methanol, saline, ethylene dichloride, chloroform, propanol, ethanol, isobutanol, formamide, methylene dichloride, butanol, acetonitrile, isopropanol, tetrahydrofuran, dioxane, chloroform / dichloromethane, methanol, hexane, and ethyl acetate.

[0104] Typically, the product of the chromatography step is collected in multiple fractions, which can then be tested for the presence of the desired compound using any suitable analytical technique (e.g., thin layer chromatography, mass spectrometry, and ultraviolet absorption). Fractions enriched in the desired compound can then be selected for further purification.

[0105] Alternatively, or in conjunction with chromatography, crystallization can be carried out to obtain highly pure amides. The solubility of hydroxycinnamic acid tyramine containing acid amides can be adjusted by changing the temperature and / or composition of the solution, for example, by removing ethanol and / or adjusting the pH to facilitate precipitation, followed by filtering or centrifuging the precipitated crystals or oil. Other suitable methods include, but are not limited to, liquid-liquid extraction, centrifugal partition chromatography, or adsorption onto a resin or removal of impurities with a resin.

[0106] A "substantially pure" preparation of a compound is defined as a preparation having a chromatographic purity (of the desired compound) of greater than 95%, more preferably greater than 96%, more preferably greater than 97%, more preferably greater than 98%, more preferably greater than 99%, and most preferably greater than 99.5%, as determined by area normalization of the HPLC profile.

[0107] The term "extract containing a compound" encompasses preparations having a chromatographic purity of at least 2%, preferably greater than 5%, and more preferably greater than 10% for the desired compound. Such extracts generally contain a greater proportion of impurities, non-target materials, and other molecules than "substantially pure" preparations.

[0108] In certain embodiments, an "extract containing a compound" is a "botanical" product or substance. In this context, "botanical" refers to "products containing plant material, algae, macroscopic fungi, and combinations thereof." The botanical is defined by the process steps used to prepare the extract (e.g., by crushing, decoction, expression, aqueous extraction, and / or ethanol extraction) and provide a quantitative amount of one or more compounds of interest.

[0109] Ideally, the compounds of the present disclosure are extracted and / or purified from plants. Exemplary plant sources include, but are not limited to, plants of the genera, families, orders, genera, and species listed in Table 1.

[0110] [Table 1]

[0111] As an illustration, an extract containing N-trans-caffeoyltyramine can be obtained by grinding or crushing the dried fruits of Tribulus terrestris, subjecting the ground material to 80% ethanol at room temperature, filtering, concentrating the 80% ethanol extract, resuspending the concentrated extract in water, partitioning the aqueous solution with hexane, adding chloroform to the aqueous layer, and subjecting the chloroform layer to liquid chromatography with silica gel. See, e.g., Ko et al. (2015) Internatl. J. Mol. Med. 36(4):1042-8.

[0112] Extracts containing tyramine-containing hydroxycinnamic acid amides can be standardized using conventional techniques such as high performance liquid chromatography (HPLC) or high performance thin layer chromatography (HPTLC). The term "standardized extract" refers to an extract that is standardized by identifying characteristic components or bioactive markers present in the extract. Characterization can be achieved, for example, by analyzing spectral data, such as mass spectrometry (MS), infrared (IR), ultraviolet (UV), and nuclear magnetic resonance (NMR) spectroscopic data.

[0113] biological activity The biological activity of the compounds and / or extracts can be determined using one or more of the well-known biological assays and animal models detailed below, each of which provides a measure of the activity of the disclosed compounds to provide beneficial effects on cellular endpoints associated with digestive health and chronic bowel diseases or disorders, including, but not limited to, IBD, irritable bowel syndrome (IBS), UC, celiac disease, and CD.

[0114] Model of epithelial barrier integrity. To assess barrier function, 3D spheroids are incubated basolaterally with plasma samples from IBS subjects or healthy controls. Medium alone and 2 mM ethylene glycol tetraacetic acid (EGTA) are used as negative and positive controls, respectively. Spheroids are incubated in 2 mL of a solution containing 37.5% (v / v) plasma, 52.5% (v / v) medium, and 10% (v / v) fluorescein isothiocyanate-labeled dextran of 4 kDa (FD4) in the presence or absence of compounds or extracts of the present disclosure. Basolateral to luminal FD4 permeation is assessed by confocal microscopy. See Ludidi et al. (2015) PLoS One 10(5):e0123498.

[0115] The EDM-monocyte coculture model can be used to assess three-way interactions between microbes, the gastrointestinal epithelium, and the immune system. See WO 2018 / 161077 A1. In this assay, EDM is prepared for coculture in two chamber slides containing IBD-associated microbes on the apical side and non-epithelial cells (immune and non-immune cells, e.g., monocytes, T cells, myofibroblasts, etc.) on the basal side, recreating a three-way system involving microbes, gastrointestinal epithelium, and the immune system. The influence of microbes on the epithelium, the latter's ability to release soluble factors on the basal side (cytokines such as MCP-1 or butyrophilin, which attack yδT cells), can be assessed while measuring how such factors induce the recruitment and activation of non-epithelial cells. Using this approach, the effects of extracts or compounds of the present disclosure on the complex interactions between gut microbes, epithelial cells, and non-epithelial cells can be assessed independently by assessing gene expression by RNA sequencing and cytokine expression by qPCR and ELISA.

[0116] Animal Models of IBS. The wrap restraint stress (WRS) model is an established model for human IBS (Williams et al. (1988) Gastroenterology 94:611-621). The WRS model involves forced immobilization of animals, typically administered once (acute testing) and lasting at least 2 hours. Efficacy of this test is confirmed by the immediate onset of hyperalgesia, quantifiable by the number of colonic-rectal distension (CRD), inhibition of small intestinal transit, stimulation of colonic activity, and increased fecal output. Additionally, rats in this assay have been shown to exhibit mild mucosal inflammation accompanied by a marked increase in mast cells and eosinophils, overlapping with that described in colon biopsies of IBS (Traini et al. (2016) Neurogastroenterol. Motil. 28:1172-1185; Traini et al. (2017) J. Cell. Mol. Med. 21:735-745). Furthermore, these animals exhibited important changes in glial cells, inhibitory and excitatory neurotransmitters and receptors that have been implicated in the movement disorders and hypersensitivity present in IBS patients. Such models are useful for demonstrating in vivo responses to compounds of the present disclosure and for addressing important concepts such as dose-response.

[0117] Animal Model of Chronic Colitis. Chronic colitis is induced by exposure to 1%-5% (wt / vol) dextran sodium sulfate (molecular weight 36,000-50,000 kDa) dissolved in drinking water (Okayasu et al. (1990) Gastroenterology 98:694-702). DSS is administered ad libitum for 5-7 days, followed by regular drinking water for several days. During DSS administration, mice develop acute colitis accompanied by ulcers, weight loss, and bloody diarrhea. Therefore, starting the day after the third DSS cycle, mice are challenged with a compound or extract of the present disclosure to demonstrate an in vivo response. Macroscopic and histological scores are assessed for the entire colon, while biochemical assays can be performed on colon segments collected from inflamed areas proximal and distal to significant necrotic damage.

[0118] Counterscreening. Counterscreening is often used to select from a library of compounds to avoid off-target effects. In the present disclosure, the activity of a compound as a modulator of HNF4α activity is the desired target, even though other off-target effects may occur. Drugs marketed for human use based on effects on targets other than HNF4α have subsequently been shown to have activity as HNF4α activators (alverine and benfluorex, Lee et al. (2013) ACS Chem. Biol. 8 (8): 1730-6). Alverine is marketed as a smooth muscle relaxant for gastrointestinal disorders, while benfluorex was marketed as an appetite suppressant. Benfluorex was known to be metabolized by cleavage of the ester moiety to fenfluramine, a potent agonist of the serotonin 5-hydroxytryptamine 2 (5-HT2) receptor, an effect thought to be related to its activity as an appetite suppressant (Porter et al. (1999) Br. J. Pharmacol. 128(1):13-20). However, modulation of the 5-HT2 receptor by benfluorex was associated with undesirable cardiopulmonary side effects. Therefore, based on experiments with synthetic compounds, the compounds and extracts of the present disclosure are tested for off-target effects on 5-hydroxytryptamine receptor activation, for example, using a Fluorescence Imaging Plate Reader (FLIPR) assay, which is useful for detecting the activity of human 5-HT2 receptors. 2A , 5-HT 2B , or 5-HT 2C This allows for rapid detection of elevated intracellular calcium levels in receptor-expressing cells and CHO-K1 cells. See, e.g., Porter et al. (1999) Br. J. Pharmacol. 128(1):13-20. Other counterscreens can be chosen based on initial studies if toxic effects may be related to other off-target actions.

[0119] Formulation A substantially pure compound or extract containing a compound of the present disclosure can be combined with a carrier and provided in any form suitable for ingestion by or administration to a subject. In this regard, the compound or extract is added to an ingestion product as an exogenous component or additive. Suitable ingestible forms include, but are not limited to, dietary supplements, food ingredients or additives, medical foods, nutraceuticals, or pharmaceutical compositions. In some embodiments, the compound or extract is provided in either liquid or powder form.

[0120] A food ingredient or food additive is an edible substance (including any substance intended for use in the creation, manufacture, packing, processing, preparation, treatment, packaging, transport, or holding of food) intended to directly or indirectly contribute to or affect the characteristics of any food. Foods, particularly functional foods, are foods that have been fortified or enriched during processing to include additional supplemental nutrients and / or beneficial ingredients. Foods according to the present disclosure can be, for example, butter, margarine, sweet or savory spreads, condiments, biscuits, health food bars, bread, cakes, cereals, candy, confectionery, soups, milk, yogurt, or fermented dairy products, cheese, fruit and vegetable-based beverages, fermented beverages, shakes, flavored waters, teas, oils, or any other suitable food form. In some embodiments, the food is a whole food product in which the concentration of a compound is enriched through specific post-harvest and food production processing methods to a level that results in an effective amount of the compound.

[0121] A dietary supplement is a product taken orally containing the compounds or extracts of the present disclosure and intended to supplement the diet. A nutraceutical is a product derived from a food source that provides additional health benefits in addition to the basic nutritional value found in food. A pharmaceutical composition is defined as any component of a drug product intended to have pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the human or other animal body. Dietary supplements, nutraceuticals, and pharmaceutical compositions can be found in many forms, such as capsules, tablets, coated tablets, pills, capsules, pellets, granules, softgels, gelcaps, liquids, powders, emulsions, suspensions, elixirs, syrups, and any other form suitable for use.

[0122] The pharmaceutical compositions disclosed herein can be prepared in a manner known per se, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes. In addition, the active ingredient is contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical preparations disclosed herein can be provided as salts with pharmaceutically compatible counterions.

[0123] Numerous techniques exist in the art for administering compounds, salts, and / or compositions, including, but not limited to, oral, rectal, intrapulmonary, topical, aerosol, injection, infusion, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injection. In some embodiments, the compounds described herein, including compounds of Formula (I), (II), (III), or pharmaceutically acceptable salts thereof, can be administered orally.

[0124] The compounds, salts, and / or compositions can also be administered in a local rather than systemic manner, for example, via injection or implantation of the compound directly into the affected area, often in a depot or sustained-release formulation. Additionally, the compounds can be administered in targeted drug delivery systems, for example, in liposomes coated with tissue-specific antibodies. Liposomes are targeted and selectively taken up by organs. For example, intranasal or intrapulmonary delivery is desirable to target respiratory diseases or conditions.

[0125] The compositions can, if desired, be presented in a pack or dispenser device that can contain one or more unit dosage forms containing the active ingredient. The pack can, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device can be accompanied by instructions for administration. The pack or dispenser can also have a notice associated with the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, the notice reflecting approval by the agency of the drug form for administration to humans or animals. Such notice can, for example, be labeling approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Compositions that can include the compounds and / or salts described herein formulated in a compatible pharmaceutical excipient can also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0126] The compounds, salts, and / or pharmaceutical compositions can be provided to the administering physician or other medical professional in the form of a kit. The kit is a package housing a container containing the compound in a suitable pharmaceutical composition and instructions for administering the pharmaceutical composition to a subject. The kit can also optionally contain one or more additional therapeutic agents. The kit can also contain divided doses of the compound or pharmaceutical composition for sequential or sequential administration. The kit can optionally contain one or more diagnostic tools and instructions for use. The kit can contain a suitable delivery device, such as a syringe, with instructions for administering the compound and any other therapeutic agents. The kit can optionally contain instructions for storage, reconstitution (if appropriate), and administration of any or all of the included therapeutic agents. The kit can contain multiple containers reflecting the number of doses to be given to a subject.

[0127] In some embodiments, the compound of Formula (I), Formula (II), or Formula (III) is administered at a dose ranging from about 1 to 200 mg / kg body weight. In some embodiments, the compound of Formula (I), Formula (II), or Formula (III) has a concentration of about 1 to 10, 1 to 20, 1 to 30, 1 to 40, 1 to 50, 1 to 60, 1 to 70, 1 to 80, 1 to 90, 1 to 100, 1 to 200, 1 to 300, 1 to 400, 1 to 500, 1 to 600, 1 to 700, 1 to 800, 1 to 900, 1 to 1000, 1 to 11, 1 to 12, 1 to 13, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, 10 to 20, 10 to 30, 10 to 40, 10 to 50, 10 to 60, 10 to 70, 10 to 80, 10-90, 10-100, 10-200, 10-300, 10-400, 10-500, 10-600, 10-700, 10-800, 10-900, 10-1000, 20-30, 20-40, 20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 20-200, 20-300, 20-400, 20-500, 20-600, 20-700, 20-800, 20-900, 20-1000, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90, 30-10 0, 30-200, 30-300, 30-400, 30-500, 30-600, 30-700, 30-800, 30-900, 30-1000, 40-50, 40-60, 40-70, 40-80, 40-90, 40-100, 40-200, 40-300, 40-400, 40-500, 40-600, 40-700, 40-800, 40-900, 40-1000, 50-60, 50-70, 50-80, 50-90, 50-100, 50-200, 50-300, 50-400, 50-500, 50-600, 50~700, 50~800, 50~900, 60~70, 60~80, 60~90, 60~100, 60~200, 60~300, 60~400, 60~500, 60~600, 60~700, 60~800, 60~900, 60~1000, 70~80, 70~90, 70~100, 70~200, 70~300, 70~400, 70~500, 70~600, 70~700, 70~800, 70~900, 70~1000, 80~90, 80~100, 80~200, 80~300, 80~400, 80~500,It is administered at a dose in the range of 80-600, 80-700, 80-800, 80-900, 80-100, 90-100, 90-200, 90-300, 90-400, 90-500, 90-600, 90-700, 90-800, 90-900, 90-1000, 100-150, 100-200, 100-300, 100-400, 100-500, 100-600, 100-700, 100-800, 100-900, or 100-1000 mg / kg body weight. In some embodiments, the compound of Formula (I), Formula (II), or Formula (III) has a concentration of about 0.01, 0.02, 0.03, 0.05, 0.07, 0.1, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18 , 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 80, 90, or 95 mg / kg body weight. In some embodiments, the compound of Formula (I), Formula (II), or Formula (III) has a concentration of about 0.01, 0.02, 0.03, 0.05, 0.07, 0.1, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 9 4.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 2 5, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40mg / 1m of body surface area, 2In some embodiments, the compound of Formula (I), Formula (II), or Formula (III) is administered at a dose of about 0.01, 0.02, 0.03, 0.05, 0.07, 0.1, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19 , 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or greater than 100 mg / kg subject body weight.

[0128] In some embodiments, the dose of the compound of Formula (I), Formula (II), or Formula (III) is about 0.1 mg to 10 mg, 0.1 mg to 25 mg, 0.1 mg to 30 mg, 0.1 mg to 50 mg, 0.1 mg to 75 mg, 0.1 mg to 100 mg, 0.5 mg to 10 mg, 0.5 mg to 25 mg, 0.5 mg to 30 mg, 0.5 mg to 50 mg, 0.5 mg to 75 mg, 0.5 mg to 100 mg, 1 mg to 10 mg, 1mg~25mg, 1mg~30mg, 1mg~50mg, 1mg~75mg, 1mg~100mg, 2mg~10mg, 2mg~25mg, 2mg~30mg, 2mg~50mg, 2mg~7 5mg, 2mg~100mg, 3mg~10mg, 3mg~25mg, 3mg~30mg, 3mg~50mg, 3mg~75mg, 3mg~100mg, 4mg~100mg, 5mg~10mg, 5mg ~25mg, 5mg~30mg, 5mg~50mg, 5mg~75mg, 5mg~300mg, 5mg~200mg, 7.5mg~15mg, 7.5mg~25mg, 7.5mg~30mg, 7.5m g~50mg, 7.5mg~75mg, 7.5mg~100mg, 7.5mg~200mg, 10mg~20mg, 10mg~25mg, 10mg~50mg, 10mg~75mg, 10mg~100m In some embodiments, the compound of Formula (I), Formula (II), or Formula (III) is administered in an amount of about 20 mg to 60 mg, 27 mg to 60 mg, 20 mg to 45 mg, or 27 mg to 45 mg. In some embodiments, the compound of Formula (I), Formula (II), or Formula (III) administered is about 1 mg to 5 mg, 1 mg to 7.5 mg, 2.5 mg to 5 mg, 2.5 mg to 7.5 mg, 5 mg to 7.5 mg, 5 mg to 9 mg, 5 mg to 10 mg, 5 mg to 12 mg, 5 mg to 14 mg, 5 mg to 15 mg, 5 mg to 16 mg, 5 mg to 18 mg, 5 mg to 20 mg, 5 mg to 22 mg, 5 mg to 24 mg,5mg~26mg、5mg~28mg、5mg~30mg、5mg~32mg、5mg~34mg、5mg~36mg、5mg~38mg、5mg~40mg、5mg~42mg、5mg~44mg、5mg~46mg、5mg~48mg、5mg~50mg、5mg~52mg、5mg~54mg、5mg~56mg、5mg~58mg、5mg~60mg、7mg~7.7mg、7mg~9mg、7mg~10mg、7mg~12mg、7mg~14mg、7mg~15mg、7mg~16mg、7mg~18mg、7mg~20mg、7mg~22mg、7mg~24mg、7mg~26mg、7mg~28mg、7mg~30mg、7mg~32mg、7mg~34mg、7mg~36mg、7mg~38mg、7mg~40mg、7mg~42mg、7mg~44mg、7mg~46mg、7mg~48mg、7mg~50mg、7mg~52mg、7mg~54mg、7mg~56mg、7mg~58mg、7mg~60mg、9mg~10mg、9mg~12mg、9mg~14mg、9mg~15mg、9mg~16mg、9mg~18mg、9mg~20mg、9mg~22mg、9mg~24mg、9mg~26mg、9mg~28mg、9mg~30mg、9mg~32mg、9mg~34mg、9mg~36mg、9mg~38mg、9mg~40mg、9mg~42mg、9mg~44mg、9mg~46mg、9mg~48mg、9mg~50mg、9mg~52mg、9mg~54mg、9mg~56mg、9mg~58mg、9mg~60mg、10mg~12mg、10mg~14mg、10mg~15mg、10mg~16mg、10mg~18mg、10mg~20mg、10mg~22mg、10mg~24mg、10mg~26mg、10mg~28mg、10mg~30mg、10mg~32mg、10mg~34mg、10mg~36mg、10mg~38mg、10mg~40mg、10mg~42mg、10mg~44mg、10mg~46mg、10mg~48mg、10mg~50mg、10mg~52mg、10mg~54mg、10mg~56mg、10mg~58mg、10mg~60mg、12mg~14mg、12mg~15mg、12mg~16mg、12mg~18mg、12mg~20mg、12mg~22mg、12mg~24mg、12mg~26mg、12mg~28mg、12mg~30mg、12mg~32mg、12mg~34mg、12mg~36mg、12mg~38mg、12mg~40mg、12mg~42mg、12mg~44mg、12mg~46mg、12mg~48mg、12mg~50mg、12mg~52mg、12mg~54mg、12mg~56mg、12mg~58mg、12mg~60mg、15mg~16mg、15mg~18mg、15mg~20mg、15mg~22mg、15mg~24mg、15mg~26mg、15mg~28mg、15mg~30mg、15mg~32mg、15mg~34mg、15mg~36mg、15mg~38mg、15mg~40mg、15mg~42mg、15mg~44mg、15mg~46mg、15mg~48mg、15mg~50mg、15mg~52mg、15mg~54mg、15mg~56mg、15mg~58mg、15mg~60mg、17mg~18mg、17mg~20mg、17mg~22mg、17mg~24mg、17mg~26mg、17mg~28mg、17mg~30mg、17mg~32mg、17mg~34mg、17mg~36mg、17mg~38mg、17mg~40mg、17mg~42mg、17mg~44mg、17mg~46mg、17mg~48mg、17mg~50mg、17mg~52mg、17mg~54mg、17mg~56mg、17mg~58mg、17mg~60mg、20mg~22mg、20mg~24mg、20mg~26mg、20mg~28mg、20mg~30mg、20mg~32mg、20mg~34mg、20mg~36mg、20mg~38mg、20mg~40mg、20mg~42mg、20mg~44mg、20mg~46mg、20mg~48mg、20mg~50mg、20mg~52mg、20mg~54mg、20mg~56mg、20mg~58mg、20mg~60mg、22mg~24mg、22mg~26mg、22mg~28mg、22mg~30mg、22mg~32mg、22mg~34mg、22mg~36mg、22mg~38mg、22mg~40mg、22mg~42mg、22mg~44mg、22mg~46mg、22mg~48mg、22mg~50mg、22mg~52mg、22mg~54mg、22mg~56mg、22mg~58mg、22mg~60mg、25mg~26mg、25mg~28mg、25mg~30mg、25mg~32mg、25mg~34mg、25mg~36mg、25mg~38mg、25mg~40mg、25mg~42mg、25mg~44mg、25mg~46mg、25mg~48mg、25mg~50mg、25mg~52mg、25mg~54mg、25mg~56mg、25mg~58mg、25mg~60mg、27mg~28mg、27mg~30mg、27mg~32mg、27mg~34mg、27mg~36mg、27mg~38mg、27mg~40mg、27mg~42mg、27mg~44mg、27mg~46mg、27mg~48mg、27mg~50mg、27mg~52mg、27mg~54mg、27mg~56mg、27mg~58mg、27mg~60mg、30mg~32mg、30mg~34mg、30mg~36mg、30mg~38mg、30mg~40mg、30mg~42mg、30mg~44mg、30mg~46mg、30mg~48mg、30mg~50mg、30mg~52mg、30mg~54mg、30mg~56mg、30mg~58mg、30mg~60mg、33mg~34mg、33mg~36mg、33mg~38mg、33mg~40mg、33mg~42mg、33mg~44mg、33mg~46mg、33mg~48mg、33mg~50mg、33mg~52mg、33mg~54mg、33mg~56mg、33mg~58mg、33mg~60mg、36mg~38mg、36mg~40mg、36mg~42mg、36mg~44mg、36mg~46mg、36mg~48mg、36mg~50mg、36mg~52mg、36mg~54mg、36mg~56mg、36mg~58mg、36mg~60mg、40mg~42mg、40mg~44mg、40mg~46mg、40mg~48mg、40mg~50mg、40mg~52mg、40mg~54mg、40mg~56mg、40mg~58mg、40mg~60mg、43mg~46mg、43mg~48mg、43mg~50mg、43mg~52mg、43mg~54mg、43mg~56mg、43mg~58mg、42mg~60mg、45mg~48mg、45mg~50mg、45mg~52mg、45mg~54mg、45mg to 56mg, 45mg to 58mg, 45mg to 60mg, 48mg to 50mg, 48mg to 52mg, 48mg to 54mg, 48mg to 56mg, 48mg to 58mg, 48mg to 60mg, 50mg to 52mg, 50mg to 54mg, 50mg to 56mg, 50mg to 58mg, 50mg to 60mg, 52mg to 54mg, 52mg to 56mg, 52mg to 58mg, or 52mg to 60mg. In some embodiments, the dose of the compound of Formula (I), Formula (II), or Formula (III) is about 0.1 mg, 0.3 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 30 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 72 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg greater than, equal to, or is about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. In some embodiments, the dose of the compound of Formula (I), Formula (II), or Formula (III) is less than about 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg.

[0129] The term "carrier," as used herein, means a substance, composition, or vehicle, such as a liquid or solid filler, excipient, additive, manufacturing aid (e.g., lubricant, magnesium talc, calcium or zinc stearate, or stearic acid), or solvent encapsulating material, that is involved in carrying or transporting a compound of interest from one organ or part of the body to another. Each carrier must be compatible with the other ingredients of the formulation and not harmful to the subject. Some examples of substances that can serve as carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, and hydroxypropylmethylcellulose; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) additives, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; and (10) gluten. (11) glycols, such as propylene glycol, (12) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol, (13) esters, such as ethyl oleate and ethyl laurate, (14) agar, (15) buffering agents, such as magnesium hydroxide and aluminum hydroxide, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) pH buffer solutions, (21) polyesters, polycarbonates, and / or polyanhydrides, and (22) other non-toxic, compatible materials utilized in conventional formulations.

[0130] To prepare solid compositions such as tablets or capsules, the compound or extract is mixed with a carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums) and other excipients (e.g., water) to form a solid composition. This solid composition is then subdivided into unit dosage forms containing an effective amount of a compound of the present disclosure. Tablets or pills containing the compound or extract can be coated or compounded to provide a dosage form offering the advantage of prolonged action.

[0131] In certain embodiments of the present disclosure, the ingestible composition comprises a compound or extract that reduces or inhibits microbial growth, a carrier, and a preservative. The preservative is added in an amount of up to about 5% by weight of the film, preferably about 0.01% to 1% by weight. Preferred preservatives include sodium benzoate, methylparaben, propylparaben, sodium nitrite, sulfur dioxide, sodium sorbate, and potassium sorbate. Other suitable preservatives include, but are not limited to, salts of edetic acid (also known as salts of ethylenediaminetetraacetic acid or EDTA, such as disodium EDTA).

[0132] The liquid forms that the compounds or extracts of the present disclosure are incorporated into for oral or parenteral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions containing edible oils, as well as elixirs and similar vehicles.Suitable dispersing or suspending agents for aqueous suspensions include synthetic natural gums, such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.The liquid preparations for oral administration can be in the form of, for example, solutions, syrups or suspensions, or can be in the form of a dry product that is reconstituted with water or other suitable vehicles before use. Such liquid preparations can be prepared by conventional means with acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol), preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid), and artificial or natural colorants and / or sweeteners.

[0133] Methods for preparing the disclosed formulations or compositions include combining a compound or extract of the present disclosure with a carrier and, optionally, one or more accessory ingredients and / or active ingredients. Generally, formulations are prepared by uniformly and intimately combining a compound or extract of the present disclosure with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product. Thus, the disclosed formulations can consist of, or consist essentially of, a compound or extract described herein in combination with a suitable carrier.

[0134] When the compounds or extracts of the present disclosure are administered to humans and animals as pharmaceuticals, nutritional supplements, or dietary supplements, they can be given on their own or in combination with an acceptable carrier as a composition containing, for example, 0.1 to 99% (more preferably 10 to 30%) of the active ingredient.

[0135] The ingestible product can be taken by a subject to provide less than 100 mg of a compound disclosed herein per day. In certain embodiments, the ingestible product provides 10-60 mg of tyramine-containing hydroxycinnamic acid amide per day. Effective amounts can be established by methods known in the art and may depend on bioavailability, toxicity, etc.

[0136] While it is contemplated that individual tyramine-containing hydroxycinnamic acid amides may be used in the ingestible products of the present disclosure, it is further contemplated that two or more of the compounds or extracts may be combined in any relative amounts to produce a custom combination of ingredients containing two or more tyramine-containing hydroxycinnamic acid amides in a desired ratio to enhance product efficacy, improve organoleptic properties, or some other measure of quality important to the end use of the product.

[0137] molecular target HNF4α (hepatocyte nuclear factor 4α) is a global nuclear transcription factor that regulates the expression of many genes involved in maintaining balanced metabolism (homeostasis). It is expressed in several tissues, including the liver, pancreas, and kidney, as well as the intestine. HNF4α is known to play diverse roles in epithelial biology, including epithelial cell organization, central regulation of epithelial morphogenesis, and intestinal epithelial homeostasis and barrier function (Cattin et al. (2009) Mol. Cell. Biol. 29(23):6294-6308; Spath and Weiss (1998) J. Cell Biol. 140:935-946). In addition, the HNF4α gene is highly expressed in the small intestine and colon, and HNF4α protein is abundant in the nuclei of mucosal epithelial cells (Jiang et al. (2003) Nucl. Recept. 1:5). Furthermore, it has been suggested that HNF4α has a protective role in IBD and that HNF4α agonists may be used to treat IBD (Chahar et al. (2014) Mol. Cell. Biol. 34:3291-3304).

[0138] Studies have shown that HNF4α is important for the expression and proper localization of tight and adhesive junction proteins (Chiba et al. (2003) Exp. Cell Res. 286:288-297; Parviz et al. (2003) Nat. Genet. 34:292-296) and the formation of intestinal microvilli (Chiba et al. (2006) J. Cell Biol. 175(6):971-980). Furthermore, HNF4α has also been described as a central regulator of intestinal epithelial protection against inflammation (Babeu and Boudreau (2014) World J. Gastroenterol. 20(1):22-30). Furthermore, HNF4α expression has been shown to be dramatically reduced in intestinal tissue from patients with Crohn's disease (CD) or ulcerative colitis (UC) (Darsigny et al. (2009) PLoS One 4:e7609; Ahn et al. (2008) Inflamm. Bowel Dis. 14:908-920).

[0139] Studies of intestine-specific HNF4α null mice have shown that they are more susceptible to the dextran sulfate sodium (DSS) model of colitis and exhibit increased intestinal permeability compared to control mice (Ahn et al. (2008) Inflamm. Bowel Dis. 14:908-920). Another study showed that mice lacking intestinal expression of both HNF4α P1 and P2 isoforms developed progressive chronic gastrointestinal inflammation similar to human IBD, suggesting that long-term reduction in HNF4α activity may promote IBD (Darsigny et al. (2009) PLoS One 4:e7609).

[0140] Alternatively, or in addition, a possible underlying pathophysiological mechanism for HNF4α's role in regulating gut permeability is that it can interact with the gut microbiota to prevent the development of chronic inflammation. In particular, evidence suggests that HNF4α is a microbially suppressed transcription factor in the gut, and that genes controlled by this regulation may include factors that could provide novel targets for IBD therapy (Davison et al. (2017) Genome Res. 27:1195-206). Furthermore, evidence has demonstrated that HNF4α expression is influenced by diet and bacteria. In particular, products of bacterial metabolism in the colon can produce fatty acids that act as ligands for HNF4α, thereby altering its expression (Qin et al. (2018) Genome Biol. 19:7). Furthermore, bile acids (or their derivatives), which are also involved in intestinal permeability (Stenman et al. (2012) World J. Gastroenterol. 18(9):923-9), can act as HNF4α ligands.

[0141] Clinical evidence further indicates that HNF4α agonists may be beneficial in the treatment of gastrointestinal disorders and diseases. Specifically, the HNF4α agonist Alverine has been approved for use in the treatment of IBS in Europe.

[0142] Chronic gastrointestinal disorders The terms "chronic gastrointestinal disorder," "gastrointestinal epithelial cell barrier dysfunction," "chronic disease associated with disruption of the intestinal epithelial barrier," and the like refer to a condition in which an individual has a chronic or recurrent immune response and inflammation of the gastrointestinal (GI) tract. The most common diseases or disorders are irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), and celiac disease. Other chronic gastrointestinal disorders include, but are not limited to, necrotizing enterocolitis, colitis of unknown etiology, chronic colitis, HIV enteropathy, Helicobacter gastritis, NSAID-enteropathic enteropathy / enteropathic enteropathy, pouchitis, discontinuous or patchy disease, ileitis, extracolonic inflammation, granulomatous inflammation due to disrupted crypts, aphthous ulcers, transmural inflammation, microscopic colitis, diverticulitis, diversion colitis, short bowel syndrome, GI mucositis, chemotherapy-induced mucositis, radiation-induced mucositis, and interstitial cystitis.

[0143] Ulcerative colitis (UC) is a disease that causes inflammation and pain called ulcers in the lining of the large intestine. The inflammation usually occurs in the rectum and lower colon, but can affect the entire colon. UC can occur in people of any age and is thought to be the result of the body's immune system responding to viruses or bacteria by causing persistent inflammation of the intestinal wall. People with ulcerative colitis have immune system abnormalities, but it has not been shown whether these abnormalities are the cause or result of the disease.

[0144] The most common symptoms of ulcerative colitis are abnormal pain and bloody diarrhea. Patients may also experience fatigue, weight loss, loss of appetite, rectal bleeding, and loss of fluids and nutrients. Approximately half of patients have mild symptoms. Others suffer from frequent fever, bloody diarrhea, nausea, and severe abdominal pain.

[0145] Crohn's disease (CD) is characterized by intestinal inflammation, intestinal strictures, and the development of intestinal fistulas; neuropathy often accompanies these symptoms. In some cases, Crohn's disease is thought to result from a weakened intestinal mucosal barrier, possibly due to genetic susceptibility and environmental factors (e.g., smoking), exposing the immune system to antigens from the gut lumen, including bacterial and food antigens. Another hypothesis is that persistent intestinal infection with pathogens such as Mycobacterium paratuberculosis, Listeria monocytogenes, abnormal Escherichia coli, or paramyxoviruses stimulates the immune response, or that symptoms result from a dysregulated immune response to ubiquitous antigens, such as the normal intestinal microbiota and the metabolites and toxins they produce.

[0146] The presence of IgA and IgG anti-Saccharomyces cerevisiae antibodies (ASCA) in serum has been found to be highly useful in diagnosing pediatric Crohn's disease. Furthermore, in active cases of Crohn's disease, high concentrations of TNF-α and IL-6 are secreted into the circulation, and TNF-α, IL-1, IL-6, and IL-8 are locally produced in excess by mucosal cells. In this regard, it has been suggested that cytokine profiles in fecal samples may be a useful diagnostic tool for Crohn's disease.

[0147] Irritable Bowel Syndrome (IBS). IBS is a disorder that primarily affects the intestines or large intestine. IBS causes cramps, bloating, gas, diarrhea, and constipation. With IBS, the nerves and muscles of the intestines are highly sensitive and can become activated during or immediately after eating or exercise, causing cramps and diarrhea. Foods that tend to trigger symptoms include dairy products, chocolate, alcohol, caffeine, carbonated drinks, and fatty foods. In some instances, symptoms can be triggered simply by eating a large meal.

[0148] Necrotizing enterocolitis. Necrotizing enterocolitis is an acquired disease, primarily in premature or sick newborns, in which intestinal tissue dies. In necrotizing enterocolitis, the lining of the intestinal wall dies and tissue is sloughed off. The cause of this disorder is unknown, but it is thought that reduced blood flow to the intestine prevents the intestine from producing the normal protective mucosa. Bacteria in the intestine may also be a cause. At risk are small, premature infants, children fed concentrated formula, children in daycare centers with sudden outbreaks (suggesting an inflammatory cause), and children receiving exchange transfusions.

[0149] Symptoms include abdominal distension, vomiting, lethargy, feeding intolerance, blood in the stool, temperature instability, and diarrhea. Diagnosis usually involves abdominal x-rays and testing for occult blood in the stool, leukocytosis, thrombocytopenia, and lactic acidosis.

[0150] Celiac Disease. Celiac disease is a digestive disorder that damages the small intestine, preventing the absorption of nutrients from food. People with celiac disease have digestive disorders and cannot tolerate gluten, a protein found in wheat, rye, and barley. When people with celiac disease eat foods containing gluten or use products containing gluten, their immune system responds by damaging the small intestine.

[0151] Celiac disease is a genetic condition that may first be triggered or occur after surgery, pregnancy, childbirth, a viral infection, or severe emotional stress. Subjects with celiac disease may present with diarrhea and abdominal pain, irritability, depression, gas, recurrent abdominal bloating, foul-smelling or fatty stools, weight loss / gain, fatigue, unexplained anemia, bone or joint pain, osteoporosis, bone deficiency, behavioral changes, tingling and numbness in the feet (due to nerve damage), muscular colic, seizures, menstrual irregularities (often caused by excessive weight loss), infertility, recurrent miscarriages, growth retardation, poor growth in children, pale sores in the mouth (called aphthous ulcers), tooth discoloration or loss of enamel, and an itchy skin rash (dermatitis herpetiformis). Celiac disease can be diagnosed using blood tests to measure levels of immunoglobulin A (IgA), anti-tissue transglutaminase (tTGA), and IgA anti-endomysial antibodies (AEA).

[0152] HIV enteropathy. HIV enteropathy is a condition in HIV-positive individuals characterized by chronic, well-established diarrhea (longer than one month in duration) without an identified inflammatory cause even after thorough evaluation. It is thought to be due to the direct or indirect action of HIV on the intestinal mucosa.

[0153] Helicobacter gastritis. Heliobacter pylori can cause stomach infections that can contribute to the development of dyspepsia (heartburn, bloating, and nausea), gastritis (stomach inflammation), and gastric and duodenal ulcers. H. pylori infection can be diagnosed by endoscopic biopsy followed by testing of the removed tissue for bacteria, a breath test, or a blood test (measuring antibodies to these bacteria present in the blood). Symptoms include discomfort, bloating, nausea, and possibly vomiting, as well as ulcers.

[0154] NSAIDs—Enteropathy / Enteritis. The anti-inflammatory, analgesic, and antipyretic properties of NSAIDs are well established, allowing their use in a wide range of disorders. A major limitation of the clinical usefulness of NSAIDs is their toxicity to the gastroduodenal epithelium. NSAID toxicity is not site-specific to the gastroduodenum and can induce toxicity in the more distal intestine.

[0155] Digestive Health The present disclosure provides methods for improving, restoring, or maintaining digestive health. According to such methods, an effective amount of a compound or extract of the present disclosure is provided to a subject in need thereof to improve or maintain the subject's digestive function, thereby addressing the underlying etiology of one or more chronic gastrointestinal disorders and promoting the subject's health, well-being, and quality of life. The term "subject," as used herein, refers to an animal, preferably a mammal. In some embodiments, the subject is a veterinary animal, a companion animal, a livestock animal, a laboratory animal, or a zoological animal. In other embodiments, the subject is a human.

[0156] In some aspects, a composition comprising a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, isomer, homodimer, heterodimer, or conjugate thereof, improves digestive health in a subject. In some embodiments, a composition comprising a compound of Formula (I), Formula (II), or Formula (III) treats or improves a digestive health-related disease or condition in a subject. In some embodiments, treating or improving a subject's digestive health is not treating or improving inflammation. In some embodiments, a composition comprising a compound of Formula (I), Formula (II), or Formula (III) treats or improves a digestive health-related disease or condition in a subject by increasing HNF4α expression. In some embodiments, a composition comprising a compound of Formula (I), Formula (II), or Formula (III) treats or improves a digestive health-related disease or condition in a subject by reversing the loss of Paneth cells resulting from a high-fat diet. In some embodiments, a composition comprising a compound of Formula (I), Formula (II), or Formula (III) treats or improves a disease or condition related to digestive health in a subject by increasing intestinal villi. In some embodiments, a composition comprising a compound of Formula (I), Formula (II), or Formula (III) treats or improves a disease or condition related to digestive health in a subject by increasing Paneth cell formation. In some embodiments, a composition comprising a compound of Formula (I), Formula (II), or Formula (III) treats or improves a disease or condition related to digestive health in a subject by reducing conditions associated with allergic reactions.

[0157] In one embodiment, a composition comprising a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, treats or improves at least one factor associated with digestive health in a subject. In other aspects, a composition comprising a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof disclosed herein, improves the digestive health of a subject, e.g., by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In still other embodiments, a composition comprising Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, is, for example, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about Improve digestive health by reducing a disease or condition associated with digestive health by 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%. In some embodiments, the disease or condition is associated with digestive health levels of Paneth cells, HNF4α levels, allergic responses, or intestinal villi levels.

[0158] In one embodiment, a composition comprising a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, has anti-inflammatory activity capable of reducing the level of inflammation in the liver or intestine. In other aspects, a composition comprising a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, disclosed herein, has anti-inflammatory activity capable of reducing the level of inflammation by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In still other embodiments, a composition comprising Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, is, for example, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, The composition has anti-inflammatory activity capable of reducing the level of inflammation in the liver or intestine by about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%. In some embodiments, the inflammation is chronic inflammation. In some embodiments, the composition reduces symptoms associated with inflammation. In some embodiments, the composition treats, reduces, or eliminates symptoms associated with inflammation in a subject. In some embodiments, the composition treats, reduces, or eliminates inflammation in a subject.

[0159] In some embodiments, inflammatory symptoms may include, but are not limited to, edema, hyperemia, erythema, bruising, tenderness, stiffness, swelling, fever, chills, nasal congestion, headache, difficulty breathing, fluid retention, blood clots, loss of appetite, increased heart rate, granuloma formation, fibrin, pus, non-viscous serous fluid, or ulcers, and pain.

[0160] In some embodiments, inflammatory conditions can be associated with a large group of unrelated disorders that underlie a variety of diseases and disorders, hi some embodiments, the immune system is often involved in inflammatory disorders, manifested in both allergic reactions and some muscle disorders, with many immune system disorders resulting in abnormal inflammation.

[0161] Subjects in need of the compositions of the present disclosure include subjects with observable symptoms of chronic gastrointestinal disorders (e.g., subjects with abdominal pain, blood in the stool, pus in the stool, fever, weight loss, frequent diarrhea, fatigue, loss of appetite, tenesmus, and rectal bleeding), as well as subjects without observable symptoms of chronic gastrointestinal disorders but who are suspected of developing a gastrointestinal disorder (i.e., subjects at risk of developing a gastrointestinal disorder).

[0162] The term "effective amount," as used herein, refers to an amount of a compound, extract, or formulation containing a compound or extract that is sufficient to significantly improve a disorder. As used herein, the term "improving" or "improved" should be broadly interpreted to encompass an improvement in an identified characteristic of a disease state, which characteristic is generally considered by those skilled in the art to correlate with or be indicative of the disease in question, compared to a control or compared to a known average amount associated with the characteristic in question. For example, "improved" gastrointestinal health associated with the application of a compound or extract of the present disclosure can be demonstrated by comparing the gastrointestinal health (e.g., abdominal symptoms, feces, fever, mass, appetite, and / or epithelial barrier integrity) of a human treated with the compound or extract to that of an untreated human. Alternatively, the gastrointestinal health of a human treated with a compound or extract of the present disclosure can be compared to the gastrointestinal health of an average human presented in scientific or medical publications known to those skilled in the art. In the present disclosure, "improved" does not necessarily require that the data be statistically significant (i.e., p<0.05), rather, any quantifiable difference indicating one value (e.g., mean treatment value) is different from another value (e.g., mean control value) can be elevated to an "improved" level.

[0163] When determining an effective amount for use in humans, consideration must be given to balancing the desired effects (benefits) against the risks associated with the use of the compound. Issues in such a risk / benefit assessment include the types of side effects observed and the likelihood of these occurring. Also taken into account is the fact that the effective amount may vary depending on factors such as the particular disorder being treated, e.g., IBD, IBS, UC, or CD, the age and physical condition of the end user, the severity of the condition, the duration of treatment, and the particular carrier utilized.

[0164] Generally, a suitable daily dose of a compound or extract of the present disclosure will be that amount of compound or extract that is the lowest effective dose to produce the desired benefit, in this case, improved digestive health and, consequently, improved overall health and well-being. Such an effective dose will generally depend on the factors described herein. For oral administration, the dose can range from about 0.0001 mg to about 10 grams per kg of body weight per day, about 5 mg to about 5 grams per kg of body weight per day, about 10 to about 2 grams per kg of body weight per day, or other suitable doses. If desired, the effective daily dose of the compound or extract can be administered as two, three, four, five, six, or more subdoses, optionally in unit dosage forms, administered separately at appropriate intervals throughout the day. In some embodiments, dosing is a single daily administration.

[0165] The compounds or extracts of the present disclosure can be used alone or in combination with a particular diet or medical standard. Illustratively, the compounds or extracts of the present disclosure can be combined with a gluten-free diet or with aminosalicylates, corticosteroids, thiopurines, methotrexate, JAK inhibitors, sphingosine 1-phosphate (SIP) receptor inhibitors, anti-integrin biologics, anti-IL12 / 23R or anti-IL23 biologics, and / or anti-tumor necrosis factor drugs or biologics.

[0166] Administration of the compounds or extracts of the present disclosure improves gastrointestinal function, thereby addressing the underlying etiology of one or more gastrointestinal disorders and promoting the health, well-being, and quality of life of the subject. Ideally, an effective amount of the compounds or extracts provides a measurable improvement in the level or activity of HNF4α activity and / or intestinal epithelial barrier and / or digestive function compared to a subject not receiving treatment. More specifically, the use of the compounds or extracts of the present disclosure preferably prevents, slows the progression of, delays, or treats intestinal disorders such as IBD, IBS, UC, and / or CD.

[0167] The following non-limiting examples are provided to further illustrate the present disclosure. [Example]

[0168] Assessment of indicators of metabolic activity: materials and methods Expression of insulin and HNF4α. RNA was purified using the RNEASY® Chromatography Separation and Isolation Kit (Qiagen) and converted to cDNA using qScript™ cDNA SuperMix (Quanta Biosciences). Q-PCR was performed on cDNA equivalent to 2 μg of RNA using an Opticon Real-Time System (MJ Research) and QPCR SuperMix (BioPioneer). All mRNA values ​​shown were normalized to 18S rRNA values ​​and are expressed as fold changes over vehicle-treated controls.

[0169] Primary antibodies. HNF4α antibody was used (#sc-6556, Santa Cruz Biotechnology, Santa Cruz, CA, and #3113, Cell Signaling Technology, Danvers, MA). For fluorescence imaging, samples were incubated with ALEXA FLUOR® 488 green fluorescent dye or rhodamine-labeled anti-mouse, rabbit, or goat antibodies, and cell nuclei were counterstained with DAPI (4',6-diamidino-2-phenylindole). Antibody alone was used for immunostaining. To ensure specificity, sections were labeled with a fluorescent control. Analysis was performed using a conventional inverted microscope (Olympus, PlanFl 40x / 0.60) or a confocal microscope equipped with a krypton / argon laser.

[0170] Bioavailability Determination. Male C57BL / 6 mice were administered N-trans-caffeoyltyramine or N-trans-feruloyltyramine via IV, intraperitoneal, or oral routes (three mice per route) (Table 2).

[0171] [Table 2]

[0172] Blood samples from each mouse were collected at 0.25, 0.5, 1, 2, 4, 6, and 24 hours post-dose. An 8 μL aliquot of blood was used for analysis. After adding 200 μL of internal standards containing 100 ng / mL labetalol, 100 ng / mL dexamethasone, 100 ng / mL tolbutamide, 100 ng / mL verapamil, 100 ng / mL glyburide, and 100 ng / mL celecoxib in ACN, the mixture was vortex mixed and centrifuged at 12,000 rpm for 15 minutes at 4°C to pellet precipitated proteins. 4 μL of the supernatant was injected for LC-MS / MS analysis. Bioavailability (%) was calculated as the AUC 0-inf (% AUC Extra <20%) or AUC 0-last (% AUC Extra >20%) was used for calculations.

[0173] pH Stability Assessment. Individual stock solutions were prepared in DMSO at a concentration of 10 mg / mL. Four different buffer solutions were prepared to achieve solutions with pH values ​​of 2, 7.4, 8.5, and 10. For each pH assay, 5 μL of stock solution was added to 245 μL of buffer solution in a 2 mL tube, vortexed, and incubated in a 37°C water bath. At each time point, 50 μL aliquots were taken, neutralized, and analyzed via HPLC analysis using a DAD detector at 280 nm. The fold change in peak area at 280 nm was analyzed at the initial and final time points, 0.5 and 72 hours, respectively. [Example]

[0174] Evaluation of compounds for activity as HNF4α agonists Given the role of HNF4α in maintaining healthy metabolism in humans, test compounds were screened for activity as HNF4α agonists (either direct or indirect effects). Using the well-known insulin promoter-reporter assay, Kiselyuk et al. (2010. J. Biomol. Screen 15(6):663-70), a library of compounds was screened for activity promoting insulin activity. They identified compound 1 as an insulin activator (Kiselyuk et al. (2012) Chem. Biol. 19(7):806-18), which was subsequently shown to have HNF4α agonist activity in an ornithine transcarbamoylase (OTC) promoter assay. The OTC promoter is known to respond to HNF4α in transient transfection assays (Inoue et al. (2002) J. Biol. Chem. 277:25257-65).

[0175] To identify plant compounds with similar biological activity to this synthetic drug (compound 1), a bioinformatics approach was employed to predict a subset of all known plant compounds targeted with the desired HNF4α agonist activity. Using several algorithms combined with training data (i.e., positive data), models were built around key features of the positive data to predict the desired biological activity. More specifically, a set of 18 synthetic compounds (e.g., compound 1) with known ability to affect HNF4α activity was included in the positive data set. These structures were used to search a database of plant compounds for chemical structures with similar structural features. Several metrics were used to measure similarity, either alone or in combination, based on concepts from the fields of graph theory and information theory.

[0176] Plant compounds in the top 10 percentile of similarity to 18 target structures were selected, and compounds predicted to be potential agonists of HNF4α activity based on their chemical structure characteristics were screened in the HNF4α assay. The screening results identified a class of plant tyramines containing tyramine-containing hydroxycinnamic acid amides (i.e., N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, and p-coumaroyltyramine) that can act as HNF4α modulators. In particular, N-trans-caffeoyltyramine was determined to be roughly one order of magnitude more potent than alverine at activating HNF4α (Figure 1). Due to the hydroxyl derivatization of both phenyl rings, N-trans-caffeoyltyramine is expected to be less lipophilic and therefore more bioavailable. Overall, the increased potency and expected improved bioavailability indicated that N-trans caffeoyltyramine and other tyramine-containing hydroxycinnamic acid amides are expected to be more desirable compounds for use in the methods disclosed herein.

[0177] Experiments were performed to demonstrate that these compounds directly regulate HNF4α activity. Specifically, we demonstrated that HNF4α gene expression was upregulated (e.g., as determined by quantitative PCR analysis) in the presence of N-trans-caffeoyltyramine and N-trans-feruloyltyramine (Figure 2). In addition, p-coumaroyltyramine also upregulated HNF4α gene expression, whereas cis-feruloyltyramine, N-coumaroyldopamine, N-trans-feruloyloctopamine, and p-coumaroyloctopamine were found to be inactive. [Example]

[0178] Assessment of compound-related toxicity Taking into account the need to balance the benefits and risks of the compounds of the present disclosure, in vivo toxicity tests are typically conducted in laboratory animals (e.g., mice, rats, dogs). Such tests are typically conducted in accordance with Good Laboratory Practice (GLP) regulations to ensure reliability and reproducibility for regulatory purposes. When compounds are administered to humans for a period of several weeks to several months or years, chronic toxicity tests (studies lasting 6 months to 1 year) are typically conducted. For compounds used in food, oral toxicity tests are recommended.

[0179] The purpose of chronic toxicity testing is to determine the toxicological profile of the test compound. In the initial phase of the study, the study is conducted in rats. A total of 160 Sprague-Dawley rats (80 males and 80 females), approximately 5-7 weeks old and weighing 80-100 g each, are randomly selected and assigned to treatment groups by mass so that the mean weights of each group do not differ significantly. The test compound or extract is administered orally to the rats at dose levels of 0.5, 1, and 2 g / kg body weight per day for 90 consecutive days. The animals are observed daily for any clinical signs of toxicity (e.g., behavioral changes, skin and hair appearance, eating and drinking, etc.). At the end of the study, the animals undergo hematological, biochemical, and histopathological evaluations consistent with standard toxicological methods.

[0180] Initial safety / toxicity assays were also performed, the collective results of which are presented in Table 3.

[0181] [Table 3] [Example]

[0182] Isolation of tyramine-containing hydroxycinnamic acid amides from plant sources. Ethanol extracts were prepared from various plant species and their tissues. Individual compounds were identified in the extracts by extracting the dried plant powder material with 95% aqueous ethanol. The ethanol extract was concentrated, adsorbed onto Celite, and dry-loaded onto a C18 solid-phase extraction column. The extract was desalted by washing with two column volumes of water, which were collected and discarded. Compounds were eluted with two column volumes of methanol, and the extract was concentrated to dryness. The extract was resuspended in 1:1 acetonitrile:water prior to analysis. A calibration curve was generated prior to analysis using synthetic standards of known concentration. A list of the sources used in the analysis is presented below in Table 4. Plants are listed in descending order for each compound, with the plants that produced the highest amounts of the compound at the top of the list and the lowest producers at the bottom.

[0183] [Table 4A]

[0184] [Table 4B]

[0185] The amounts of N-trans-caffeoyltyramine, N-trans-feruloyltyramine, and p-coumaroyltyramine present in a given ethanolic extract (% of extract, w / w) were determined. Quantification of the compounds was performed by normalizing the results by the mass of the ethanolic extract (Figure 3). [Example]

[0186] N-trans-caffeoyltyramine improves tight junctions TNF-α is a proinflammatory cytokine that increases intestinal tight junction permeability. To analyze the effects of N-trans-caffeoyltyramine on tight junctions, 200 or 300 ng of TNF-α was added to epithelial CaCo-2 cell monolayers to induce tight junction damage. After TNF-α exposure, N-trans-caffeoyltyramine was added, and tight junction formation was determined by antibody staining for zonula occludens (ZO)-1. Nuclear staining (DAPI) was used to demonstrate cell viability. CaCo-2 cells were sorted for high TNF-α expression, which indicated compromised tight junction integrity. Increasing the concentration of exogenous TNF-α from 200 to 300 ng reduced ZO-1 staining. However, addition of N-trans-caffeoyltyramine reversed the effects of TNF-α on ZO-1 at both doses (200 and 300 ng).

[0187] To confirm the in vivo effects of caffeoyltyramine, 14 C57BL / 6 mice were intraperitoneally injected (IP) twice daily for several days with caffeoyltyramine. Intestinal samples were collected and stained to visualize HNFα expression, ZO-1, and DAPI staining. HNF4α expression was observed in stem cells in the epithelial layer of all mice. The expansion of HNF4α expression along the epithelial villi was visible two weeks after treatment with N-trans-caffeoyltyramine, demonstrating that this compound induced HNF4α expression in the intestinal lining of N-trans-caffeoyltyramine-treated mice. [Example]

[0188] Effects of N-trans-caffeoyltyramine on the intestine Intestines from mice treated with DMSO or N-trans-caffeoyltyramine were examined histologically. Gross morphological appearance was unchanged. DIO mice did not exhibit significant changes in HNF4α expression. In both mice, HNF4α was highly expressed in the crypts and barely detectable in the villi (see Figure 4). N-trans-caffeoyltyramine induced a large increase in overall HNF4α expression, with a large increase in the villi and a smaller increase in the crypts when expression was already fully potent (see Figure 5, quantification in the bottom panel). Analysis of genes induced by N-trans-caffeoyltyramine suggested that N-trans-caffeoyltyramine may promote the formation and / or function of Paneth cells. Paneth cells specialize as secretory cells that play an important role in defense against intestinal microorganisms. To this end, they secrete various antimicrobial peptides. Notably, Paneth cells play an important role in the pathogenesis of IBD. A high-fat diet has been reported to reduce the number of Paneth cells, and our study replicated this finding (see Figure 4), although the mechanism by which this occurs is not understood. Remarkably, N-trans-caffeoyltyramine induced a complete recovery in the number of Paneth cells in DIO mice (see Figure 4).

[0189] The present disclosure has generally been described herein using assertive language to describe many embodiments. The present disclosure also includes embodiments that entirely or partially exclude subject matter, such as substances or materials, method steps and conditions, protocols, or procedures. Various other omissions, additions, and modifications may be made in the methods and structures described above without departing from the scope of the claimed subject matter. All such variations and modifications are intended to be within the scope of the subject matter as defined in the appended claims.

[0190] With respect to the use of substantially any plural and / or singular form herein, those skilled in the art can translate from plural to singular and / or from singular to plural as appropriate to the context and / or application. Various singular / plural permutations may be expressly set forth herein for clarity.

[0191] In general, those skilled in the art will understand that the terms used herein, particularly in the appended claims (e.g., the body of the appended claims), are intended as "open" terms throughout (e.g., the term "including" should be interpreted as "including, but not limited to," the term "having" should be interpreted as "having at least," the term "comprises" should be interpreted as "including, but not limited to," etc.). Furthermore, those skilled in the art will understand that where a specific number of introduced claim recitations is intended, such intention will be explicitly stated in the claim, and that in the absence of such statement, no such intention is intended. For example, to aid in understanding, the following appended claims may contain the use of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be construed as implying that introducing a claim recitation with the indefinite article "a" or "an" limits any particular claim containing such an introduced claim recitation to embodiments containing only such a recitation, even when that same claim includes the preamble "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" should be interpreted to mean "at least one" or "one or more"); the same applies to the use of definite articles in introduced claim recitations. Additionally, those skilled in the art will recognize that even when a specific number of introduced claim recitations is explicitly recited, such a recitation should be interpreted to mean at least the recited number (e.g., a recitation of merely "two enumerations," without any other modifier, means at least two enumerations, or more than two enumerations).Furthermore, in instances where a convention similar to "at least one of A, B, and C, etc." is used, such construction is generally intended to mean that one of ordinary skill in the art would understand the convention (e.g., "a system having at least one of A, B, and C" includes, but is not limited to, a system having only A, a system having only B, a system having only C, a system having A and B together, a system having A and C together, a system having B and C together, and / or a system having A, B, and C together, etc.). In instances where a convention similar to "at least one of A, B, or C, etc." is used, such construction is generally intended to mean that one of ordinary skill in the art would understand the convention (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, a system having only A, a system having only B, a system having only C, a system having A and B together, a system having A and C together, a system having B and C together, and / or a system having A, B, and C together, etc.). Furthermore, those skilled in the art will understand that substantially any adjacent word and / or phrase expressing two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibility of including one of the terms, either of the terms, or both terms. For example, the phrase "A or B" will be understood to include the possibilities of "A," or "B," or "A and B."

[0192] Additionally, when features or aspects of the disclosure are described in terms of a Markush group, those skilled in the art will recognize that the disclosure is also hereby described in terms of any individual member or subgroup of members of the Markush group.

[0193] As will be understood by those skilled in the art, for all purposes, such as for providing descriptive information, all ranges disclosed herein also encompass all possible subranges and combinations of subranges. It can be readily recognized that any recited range fully describes and allows for division of that same range into at least two, three, four, five, ten, etc. divisions. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, a middle third, an upper third, etc. As will also be understood by those skilled in the art, all language such as "up to," "at least," "greater than," "less than," etc., refers to a range that is inclusive of the recited number and can then be broken down into subranges as described above. Finally, as will be understood by those skilled in the art, a range includes each individual numerical value. Thus, for example, a group having 1 to 3 items refers to a group having 1, 2, or 3 items. Similarly, for example, a group having 1 to 5 items refers to a group having 1, 2, 3, 4, or 5, etc. items.

[0194] While various aspects and embodiments are disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for illustrative purposes only and are not intended to limit the true scope and spirit of the invention, as set forth in the following claims.

Claims

[Claim 1] 1. A method for improving digestive health, comprising administering to a subject a composition comprising at least one carrier and a compound of formula (I): 【Chemistry 1】 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted -(O)C 1～6 Alkyl, optionally substituted -(O)C 1～6 Alkenyl, optionally substituted -(O)C 1～6 Alkynyl, optionally substituted -(O)C 4～12 Cycloalkyl, optionally substituted -(O)C 1～6 Alkyl C 4～12 Cycloalkyl, optionally substituted -(O)C 4～12 Heterocyclyl, optionally substituted -(O)C 1～6 Alkyl C 4～12 Heterocyclyl, optionally substituted -(O)C 4～12 Aryl, optionally substituted -(O)C 1～6 Alkyl C 5～12 Aryl, optionally substituted -(O)C 1～12 Heteroaryl and optionally substituted -(O)C 1～6 Alkyl C 1～12 heteroaryl, wherein the dashed bond is present or absent; X is CH 2 or O, Z is CHR a , N.R. a , or O, R a is hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amide, optionally substituted N-amide, optionally substituted ester, optionally substituted -(O)C 1～6 Alkyl, optionally substituted -(O)C 1～6 Alkenyl, optionally substituted -(O)C 1～6 Alkynyl, optionally substituted -(O)C 4～12 Cycloalkyl, optionally substituted -(O)C 1～6 Alkyl C 4～12 Cycloalkyl, optionally substituted -(O)C 4～12 Heterocyclyl, optionally substituted -(O)C 1～6 Alkyl C 4～12 Heterocyclyl, optionally substituted -(O)C 4～12 Aryl, optionally substituted -(O)C 1～6 Alkyl C 5～12 Aryl, optionally substituted -(O)C 1～12 Heteroaryl and optionally substituted -(O)C 1～6 Alkyl C 1～12 heteroaryl) or an isomer, salt, homodimer, heterodimer, or conjugate thereof, thereby improving digestive health. A method comprising:

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