AccScience Publishing / GPD / Online First / DOI: 10.36922/gpd.5058
Submit to GPD
Cite this article
14
Download
469
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
REVIEW ARTICLE

Advancements in intestinally restricted drugs: Applications, targets, and design strategies

Ke Zhang1 ,  Haixin Chen1 ,  Shengjie Li2 ,  Menglin Wan1 ,  Peilin Huo1 ,  Kai Tang1 ,  Jing Xie3 ,  Chang Liu3 ,  Shizhen Zhao1,3* ,  Xinrui Lv1*
Show Less
1 The First Affiliated Hospital of Henan University, Kaifeng, Henan, China
2 School of Pharmacy, Henan University, Kaifeng, Henan, China
3 Key Laboratory of Receptors-Mediated Gene Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, China
GPD, 5058 https://doi.org/10.36922/gpd.5058
Submitted: 7 October 2024 | Revised: 16 January 2025 | Accepted: 22 January 2025 | Published: 17 February 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Download PDF
Cite
XML
Abstract

Drug safety is of paramount importance in the pharmaceutical industry, as it often hinders the successful introduction of new drug candidates into the market. Intestinally restricted drugs, also known as non-systemic drugs, are orally administered compounds that exert therapeutic effects specifically within the intestinal lumen, thereby circumventing side effects associated with systemic exposure. These drugs offer innovative solutions for unmet medical needs in drug development while minimizing toxicity risks. This review provides an overview of the applications of intestinally restricted drugs for inflammatory diseases, irritable bowel syndrome, colorectal cancer, and other digestive system ailments. Based on design strategies, these drugs can be classified into five categories, including high molecular weight compounds, highly polar or positively charged compounds, highly lipophilic and low water solubility compounds, intestinal soft drugs, and intestinal prodrugs. Specifically, it focuses on the design strategies of these drugs and presents an analysis of these strategies through representative drugs from each category. Due to the complex physiological environment of the gastrointestinal tract and the need for precise drug targeting, developing orally administered intestinally restricted drugs remains a significant challenge for scientists. This review enhances understanding of intestinally restricted drugs and offers a valuable reference for advancing their development.

Graphical abstract
Keywords
Intestinally restricted drugs
Design strategies
Non-systemic drugs
Drug safety
Funding
This work was supported by the National Natural Science Foundation of China (Grant No. 81903444), the Key Science and Technology Program of Henan Province (Grant No. 232102310398), the Natural Science Foundation of Henan (Grant No. 242300420100), the Key Scientific Research Projects of Institutions of Higher Education in Henan Province (Grant No. 24A350004), the Medical Scientific and Technological Research Project of Henan Province (Grant No. SBCJ202303040), the Foundation of Science & Technology Department of Henan (Grant No. 202102310034), the Science and Technology Research Project of Kaifeng City (Grant No. 2303002), and the College Students’ Innovative Entrepreneurial Training Plan Program (Grant No. 20231022006).
Conflict of interest
The authors declare they have no competing interests.
References
  1. Muller PY, Milton MN. The determination and interpretation of the therapeutic index in drug development. Nat Rev Drug Discov. 2012;11(10):751-761. doi: 10.1038/nrd3801

 

  1. Ritchie TJ, Luscombe CN, Macdonald SJ. Analysis of the calculated physicochemical properties of respiratory drugs: Can we design for inhaled drugs yet? J Chem Inf Model. 2009;49(4):1025-1032. doi: 10.1021/ci800429e

 

  1. Norman P. Investigational p38 inhibitors for the treatment of chronic obstructive pulmonary disease. Expert Opin Investig Drugs. 2015;24(3):383-392. doi: 10.1517/13543784.2015.1006358

 

  1. Millan DS, Bunnage ME, Burrows JL, et al. Design and synthesis of inhaled p38 inhibitors for the treatment of chronic obstructive pulmonary disease. J Med Chem. 2011;54(22):7797-7814. doi: 10.1021/jm200677b

 

  1. Glossop PA, Lane CA, Price DA, et al. Inhalation by design: Novel ultra-long-acting β(2)-adrenoreceptor agonists for inhaled once-daily treatment of asthma and chronic obstructive pulmonary disease that utilize a sulfonamide agonist headgroup. J Med Chem. 2010;53(18):6640-6652. doi: 10.1021/jm1005989

 

  1. Sawynok J. Topical and peripherally acting analgesics. Pharmacol Rev. 2003;55(1):1-20. doi: 10.1124/pr.55.1.1

 

  1. Hirsch S, Corradini L, Just S, Arndt K, Doods H. The CGRP receptor antagonist BIBN4096BS peripherally alleviates inflammatory pain in rats. Pain. 2013;154(5):700-707. doi: 10.1016/j.pain.2013.01.002

 

  1. Small DS, Acheampong A, Reis B, et al. Blood concentrations of cyclosporin a during long-term treatment with cyclosporin a ophthalmic emulsions in patients with moderate to severe dry eye disease. J Ocul Pharmacol Ther. 2002;18(5):411-418. doi: 10.1089/10807680260362696

 

  1. Bodor N, Buchwald P. Ophthalmic drug design based on the metabolic activity of the eye: Soft drugs and chemical delivery systems. AAPS J. 2005;7(4):E820-E833. doi: 10.1208/aapsj070479

 

  1. Doukas J, Mahesh S, Umeda N, et al. Topical administration of a multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinal edema. J Cell Physiol. 2008;216(1):29-37. doi: 10.1002/jcp.21426

 

  1. Huang JF, Yafawi R, Zhang M, et al. Immunomodulatory effect of the topical ophthalmic Janus kinase inhibitor tofacitinib (CP-690,550) in patients with dry eye disease. Ophthalmology. 2012;119(7):e43-e50. doi: 10.1016/j.ophtha.2012.03.017

 

  1. Simpson KL, Markham A. Ofloxacin otic solution: A review of its use in the management of ear infections. Drugs. 1999;58(3):509-531. doi: 10.2165/00003495-199958030-00019

 

  1. Reinisch W, Hébuterne X, Buisson A, et al. Safety, pharmacokinetic, and pharmacodynamic study of sibofimloc, a novel FimH blocker in patients with active Crohn’s disease. J Gastroenterol Hepatol. 2022;37(5):832-840. doi: 10.1111/jgh.15828

 

  1. Zhang Z, Ghosh A, Connolly PJ, et al. Gut-restricted selective cyclooxygenase-2 (COX-2) inhibitors for chemoprevention of colorectal cancer. J Med Chem. 2021;64(15):11570-11596. doi: 10.1021/acs.jmedchem.1c00890

 

  1. Chaudhari SN, Harris DA, Aliakbarian H, et al. Bariatric surgery reveals a gut-restricted TGR5 agonist with anti-diabetic effects. Nat Chem Biol. 2021;17(1):20-29. doi: 10.1038/s41589-020-0604-z

 

  1. Wu Y, Aquino CJ, Cowan DJ, et al. Discovery of a highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 diabetes. J Med Chem. 2013;56(12):5094-5114. doi: 10.1021/jm400459m

 

  1. Fang S, Suh JM, Reilly SM, et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. 2015;21(2):159-165. doi: 10.1038/nm.3760

 

  1. Leonard KA, Madge LA, Krawczuk PJ, et al. Discovery of a gut-restricted JAK inhibitor for the treatment of inflammatory bowel disease. J Med Chem. 2020;63(6):2915-2929. doi: 10.1021/acs.jmedchem.9b01439

 

  1. Leber A, Hontecillas R, Zoccoli-Rodriguez V, et al. The safety, tolerability, and pharmacokinetics profile of BT-11, an oral, gut-restricted lanthionine synthetase C-like 2 agonist investigational new drug for inflammatory bowel disease: A randomized, double-blind, placebo-controlled phase I clinical trial. Inflamm Bowel Dis. 2020;26(4):643-652. doi: 10.1093/ibd/izz094

 

  1. Dodd J, Jordan R, Makhlina M, et al. A novel oral formulation of the melanocortin-1 receptor agonist PL8177 resolves inflammation in preclinical studies of inflammatory bowel disease and is gut restricted in rats, dogs, and humans. Front Immunol. 2023;14:1083333. doi: 10.3389/fimmu.2023.1083333

 

  1. Alqahtani MS, Kazi M, Alsenaidy MA, Ahmad MZ. Advances in oral drug delivery. Front Pharmacol. 2021;12:618411. doi: 10.3389/fphar.2021.618411

 

  1. Filipski KJ, Varma MV, El-Kattan AF, et al. Intestinal targeting of drugs: Rational design approaches and challenges. Curr Top Med Chem. 2013;13(7):776-802. doi: 10.2174/1568026611313070002

 

  1. Charmot D. Non-systemic drugs: A critical review. Curr Pharm Des. 2012;18(10):1434-1445. doi: 10.2174/138161212799504858

 

  1. Ferro JM, Oliveira Santos M. Neurology of inflammatory bowel disease. J Neurol Sci. 2021;424:117426. doi: 10.1016/j.jns.2021.117426

 

  1. Shah BM, Palakurthi SS, Khare T, Khare S, Palakurthi S. Natural proteins and polysaccharides in the development of micro/nano delivery systems for the treatment of inflammatory bowel disease. Int J Biol Macromol. 2020;165(Pt A):722-737. doi: 10.1016/j.ijbiomac.2020.09.214

 

  1. Seyedian SS, Nokhostin F, Malamir MD. A review of the diagnosis, prevention, and treatment methods of inflammatory bowel disease. J Med Life. 2019;12(2):113-122. doi: 10.25122/jml-2018-0075

 

  1. Shan Y, Lee M, Chang EB. The gut microbiome and inflammatory bowel diseases. Annu Rev Med. 2022;73:455-468. doi: 10.1146/annurev-med-042320-021020

 

  1. Neavin DR, Liu D, Ray B, Weinshilboum RM. The role of the aryl hydrocarbon receptor (AHR) in immune and inflammatory diseases. Int J Mol Sci. 2018;19(12):3851. doi: 10.3390/ijms19123851

 

  1. Ngui IQH, Perera AP, Eri R. Does NLRP3 inflammasome and aryl hydrocarbon receptor play an interlinked role in bowel inflammation and colitis-associated colorectal cancer? Molecules. 2020;25(10):2427. doi: 10.3390/molecules25102427

 

  1. Elhag DA, Kumar M, Saadaoui M, et al. Inflammatory bowel disease treatments and predictive biomarkers of therapeutic response. Int J Mol Sci. 2022;23(13):6966. doi: 10.3390/ijms23136966

 

  1. Han F, Ning M, Wang K, et al. Design and exploration of gut-restricted bifunctional molecule with TGR5 agonistic and DPP4 inhibitory effects for treating ulcerative colitis. Eur J Med Chem. 2022;242:114697. doi: 10.1016/j.ejmech.2022.114697

 

  1. Cui X, Teng Y, Hu Y, Li Q, Pei H, Yang Z. Therapeutic potential of a synthetic dual JAK1/TYK2 inhibitor in inflammatory bowel disease. Int Immunopharmacol. 2023;126:111238. doi: 10.1016/j.intimp.2023.111238

 

  1. Sebastián Domingo JJ. Irritable bowel syndrome. Med Clin (Barc). 2022;158(2):76-81. doi: 10.1016/j.medcli.2021.04.029

 

  1. Yoon SL, Grundmann O, Koepp L, Farrell L. Management of irritable bowel syndrome (IBS) in adults: Conventional and complementary/alternative approaches. Altern Med Rev. 2011;16(2):134-151.

 

  1. Steinbrecher KA. The multiple roles of guanylate cyclase C, a heat stable enterotoxin receptor. Curr Opin Gastroenterol. 2014;30(1):1-6. doi: 10.1097/mog.0000000000000020

 

  1. Rao SS, Go JT. Update on the management of constipation in the elderly: New treatment options. Clin Interv Aging. 2010;5:163-171. doi: 10.2147/cia.s8100

 

  1. Bassotti G, Usai Satta P, Bellini M. Plecanatide for the treatment of chronic idiopathic constipation in adult patients. Expert Rev Clin Pharmacol. 2019;12(11):1019-1026. doi: 10.1080/17512433.2019.1670057

 

  1. Feng B, Guo T. Visceral pain from colon and rectum: The mechanotransduction and biomechanics. J Neural Transm (Vienna). 2020;127(4):415-429. doi: 10.1007/s00702-019-02088-8

 

  1. Saha L. Irritable bowel syndrome: pathogenesis, diagnosis, treatment, and evidence-based medicine. World J Gastroenterol. 2014;20(22):6759-6773. doi: 10.3748/wjg.v20.i22.6759

 

  1. Padhi S, Nayak AK, Behera A. Type II diabetes mellitus: A review on recent drug based therapeutics. Biomed Pharmacother. 2020;131:110708. doi: 10.1016/j.biopha.2020.110708

 

  1. Tachibana K, Yamasaki D, Ishimoto K, Doi T. The role of PPARs in cancer. PPAR Res. 2008;2008:102737. doi: 10.1155/2008/102737

 

  1. Lefèvre L, Galès A, Olagnier D, et al. PPARγ ligands switched high fat diet-induced macrophage M2b polarization toward M2a thereby improving intestinal Candida elimination. PLoS One. 2010;5(9):e12828. doi: 10.1371/journal.pone.0012828

 

  1. Hakak Y, Shrestha D, Goegel MC, Behan DP, Chalmers DT. Global analysis of G-protein-coupled receptor signaling in human tissues. FEBS Lett. 2003;550(1-3):11-17. doi: 10.1016/s0014-5793(03)00762-2

 

  1. Sebastiani G, Ceccarelli E, Castagna MG, Dotta F. G-protein-coupled receptors (GPCRs) in the treatment of diabetes: Current view and future perspectives. Best Pract Res Clin Endocrinol Metab. 2018;32(2):201-213. doi: 10.1016/j.beem.2018.02.005

 

  1. Brown E, Heerspink HJL, Cuthbertson DJ, Wilding JPH. SGLT2 inhibitors and GLP-1 receptor agonists: Established and emerging indications. Lancet. 2021;398(10296):262-276. doi: 10.1016/s0140-6736(21)00536-5

 

  1. Chiang JY. Recent advances in understanding bile acid homeostasis. F1000Res. 2017;6:2029. doi: 10.12688/f1000research.12449.1

 

  1. Finn PD, Rodriguez D, Kohler J, et al. Intestinal TGR5 agonism improves hepatic steatosis and insulin sensitivity in Western diet-fed mice. Am J Physiol Gastrointest Liver Physiol. 2019;316(3):G412-G424. doi: 10.1152/ajpgi.00300.2018

 

  1. Wang XX, Wang D, Luo Y, et al. FXR/TGR5 dual agonist prevents progression of nephropathy in diabetes and obesity. J Am Soc Nephrol. 2018;29(1):118-137. doi: 10.1681/asn.2017020222

 

  1. Zhu Y, Xian X, Wang Z, et al. Research progress on the relationship between atherosclerosis and inflammation. Biomolecules. 2018;8(3):80. doi: 10.3390/biom8030080

 

  1. Verhaar BJH, Prodan A, Nieuwdorp M, Muller M. Gut microbiota in hypertension and atherosclerosis: A review. Nutrients. 2020;12(10):2982. doi: 10.3390/nu12102982

 

  1. Rath S, Heidrich B, Pieper DH, Vital M. Uncovering the trimethylamine-producing bacteria of the human gut microbiota. Microbiome. 2017;5(1):54. doi: 10.1186/s40168-017-0271-9

 

  1. Russell LE, Harrison WJ, Bahta AW, Zouboulis CC, Burrin JM, Philpott MP. Characterization of liver X receptor expression and function in human skin and the pilosebaceous unit. Exp Dermatol. 2007;16(10):844-852. doi: 10.1111/j.1600-0625.2007.00612.x

 

  1. Griffett K, Hayes M, Bedia-Diaz G, et al. Antihyperlipidemic activity of gut-restricted LXR inverse agonists. ACS Chem Biol. 2022;17(5):1143-1154. doi: 10.1021/acschembio.2c00057

 

  1. Sparks SM, Zhou H, Generaux C, et al. Identification of nonabsorbable inhibitors of the scavenger receptor-BI (SR-BI) for tissue-specific administration. Bioorg Med Chem Lett. 2016;26(8):1901-1904. doi: 10.1016/j.bmcl.2016.03.025

 

  1. Masson D, Koseki M, Ishibashi M, et al. Increased HDL cholesterol and apoA-I in humans and mice treated with a novel SR-BI inhibitor. Arterioscler Thromb Vasc Biol. 2009;29(12):2054-2060. doi: 10.1161/atvbaha.109.191320

 

  1. Jüngst C, Lammert F. Cholestatic liver disease. Dig Dis. 2013;31(1):152-154. doi: 10.1159/000347210

 

  1. Karpen SJ, Kelly D, Mack C, Stein P. Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders. Hepatol Int. 2020;14(5):677-689. doi: 10.1007/s12072-020-10070-w

 

  1. Li M, Wang Q, Li Y, et al. Apical sodium-dependent bile acid transporter, drug target for bile acid related diseases and delivery target for prodrugs: Current and future challenges. Pharmacol Ther. 2020;212:107539. doi: 10.1016/j.pharmthera.2020.107539

 

  1. Shirley M. Maralixibat: First approval. Drugs. 2022;82(1):71-76. doi: 10.1007/s40265-021-01649-0

 

  1. Shneider BL, Spino C, Kamath BM, et al. Placebo-controlled randomized trial of an intestinal bile salt transport inhibitor for pruritus in alagille syndrome. Hepatol Commun. 2018;2(10):1184-1198. doi: 10.1002/hep4.1244

 

  1. Al-Dury S, Marschall HU. Ileal bile acid transporter inhibition for the treatment of chronic constipation, cholestatic pruritus, and NASH. Front Pharmacol. 2018;9:931. doi: 10.3389/fphar.2018.00931

 

  1. Wagner M, Zollner G, Trauner M. New molecular insights into the mechanisms of cholestasis. J Hepatol. 2009;51(3):565-580. doi: 10.1016/j.jhep.2009.05.012

 

  1. Bertolini A, Fiorotto R, Strazzabosco M. Bile acids and their receptors: Modulators and therapeutic targets in liver inflammation. Semin Immunopathol. 2022;44(4):547-564. doi: 10.1007/s00281-022-00935-7

 

  1. Baidoun F, Elshiwy K, Elkeraie Y, et al. Colorectal cancer epidemiology: Recent trends and impact on outcomes. Curr Drug Targets. 2021;22(9):998-1009. doi: 10.2174/1389450121999201117115717

 

  1. Si H, Yang Q, Hu H, Ding C, Wang H, Lin X. Colorectal cancer occurrence and treatment based on changes in intestinal flora. Semin Cancer Biol. 2021;70:3-10. doi: 10.1016/j.semcancer.2020.05.004

 

  1. Hashemi Goradel N, Najafi M, Salehi E, Farhood B, Mortezaee K. Cyclooxygenase-2 in cancer: A review. J Cell Physiol. 2019;234(5):5683-5699. doi: 10.1002/jcp.27411

 

  1. Mohammadi H, Sahai E. Mechanisms and impact of altered tumour mechanics. Nat Cell Biol. 2018;20(7):766-774. doi: 10.1038/s41556-018-0131-2

 

  1. Comberiati P, Di Cicco M, Paravati F, et al. The role of gut and lung microbiota in susceptibility to tuberculosis. Int J Environ Res Public Health. 2021;18(22):12220. doi: 10.3390/ijerph182212220

 

  1. Dorel R, Wong AR, Crawford JJ. Trust your gut: Strategies and tactics for intestinally restricted drugs. ACS Med Chem Lett. 2023;14(3):233-243. doi: 10.1021/acsmedchemlett.3c00001

 

  1. Yusof I, Shah F, Hashimoto T, Segall MD, Greene N. Finding the rules for successful drug optimisation. Drug Discov Today. 2014;19(5):680-687. doi: 10.1016/j.drudis.2014.01.005

 

  1. Cao H, Wang K, Ye YL, Shen JH. Orally administrated small molecule drugs with intestine targeted profile: Recent development and prospects. Curr Med Chem. 2017;24(35):3921-3937. doi: 10.2174/0929867324666170810154414

 

  1. Fyfe MC. Non-systemic intestine-targeted drugs. Prog Med Chem. 2016;55:1-44. doi: 10.1016/bs.pmch.2015.10.001

 

  1. Bodor M. Development and clinical success of novel soft drugs. Orv Hetil. 2020;161(10):363-373. Uj lagy gyogyszerek kifejlesztese es klinikai sikere. doi: 10.1556/650.2020.31657

 

  1. Zawilska JB, Wojcieszak J, Olejniczak AB. Prodrugs: A challenge for the drug development. Pharmacol Rep. 2013;65(1):1-14. doi: 10.1016/s1734-1140(13)70959-9

 

  1. Glavinas H, Krajcsi P, Cserepes J, Sarkadi B. The role of ABC transporters in drug resistance, metabolism and toxicity. Curr Drug Deliv. 2004;1(1):27-42. doi: 10.2174/1567201043480036

 

  1. Chey WD, Lembo AJ, Rosenbaum DP. Tenapanor treatment of patients with constipation-predominant irritable bowel syndrome: A phase 2, randomized, placebo-controlled efficacy and safety trial. Am J Gastroenterol. 2017;112(5):763-774. doi: 10.1038/ajg.2017.41

 

  1. King AJ, Siegel M, He Y, et al. Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability. Sci Transl Med. 2018;10(456):eaam6474. doi: 10.1126/scitranslmed.aam6474

 

  1. Markham A. Tenapanor: First approval. Drugs. 2019;79(17):1897-1903. doi: 10.1007/s40265-019-01215-9

 

  1. Jacobs JW, Leadbetter MR, Bell N, et al. Discovery of tenapanor: A first-in-class minimally systemic inhibitor of intestinal Na(+)/H(+) exchanger isoform 3. ACS Med Chem Lett. 2022;13(7):1043-1051. doi: 10.1021/acsmedchemlett.2c00037

 

  1. Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002;45(12):2615-2623. doi: 10.1021/jm020017n

 

  1. Rosenbaum DP, Yan A, Jacobs JW. Pharmacodynamics, safety, and tolerability of the NHE3 inhibitor tenapanor: Two trials in healthy volunteers. Clin Drug Investig. 2018;38(4):341-351. doi: 10.1007/s40261-017-0614-0

 

  1. Duan H, Ning M, Zou Q, et al. Discovery of intestinal targeted TGR5 agonists for the treatment of type 2 diabetes. J Med Chem. 2015;58(8):3315-3328. doi: 10.1021/jm500829b

 

  1. Ullmer C, Alvarez Sanchez R, Sprecher U, et al. Systemic bile acid sensing by G protein-coupled bile acid receptor 1 (GPBAR1) promotes PYY and GLP-1 release. Br J Pharmacol. 2013;169(3):671-684. doi: 10.1111/bph.12158

 

  1. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132(6):2131-2157. doi: 10.1053/j.gastro.2007.03.054

 

  1. Ma SY, Ning MM, Zou QA, et al. OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition. Acta Pharmacol Sin. 2016;37(10):1359-1369. doi: 10.1038/aps.2016.27

 

  1. Cimolai N. Does oral vancomycin use necessitate therapeutic drug monitoring? Infection. 2020;48(2):173-182. doi: 10.1007/s15010-019-01374-7

 

  1. Niedzielski M, Broncel M, Gorzelak-Pabis P, Wozniak E. New possible pharmacological targets for statins and ezetimibe. Biomed Pharmacother. 2020;129:110388. doi: 10.1016/j.biopha.2020.110388

 

  1. Dolezelova E, Stein E, Derosa G, Maffioli P, Nachtigal P, Sahebkar A. Effect of ezetimibe on plasma adipokines: A systematic review and meta-analysis. Br J Clin Pharmacol. 2017;83(7):1380-1396. doi: 10.1111/bcp.13250

 

  1. Nussbaumer B, Glechner A, Kaminski-Hartenthaler A, Mahlknecht P, Gartlehner G. Ezetimibe-statin combination therapy. Dtsch Arztebl Int. 2016;113(26):445-453. doi: 10.3238/arztebl.2016.0445

 

  1. Jaehne G, Frick W, Lindenschmidt A, et al. Novel diphenyl azetidinone with improved physiological characteristics, corresponding production method, medicaments containing said compound and use of the latter. Patent Application WO2004087655A1; 2004.

 

  1. Kerns EH, Di L. Drug-like Properties: Concepts, Structure Design and Methods. United States: Academic Press; 2008. p. xviii-xix.

 

  1. Wang Y, Dai K, Xie K, Weng C. Biosynthesis and regulatory mechanism of acarbose and its structural analogs: A review. Sheng Wu Gong Cheng Xue Bao. 2022;38(2):605-619. doi: 10.13345/j.cjb.210248

 

  1. Clissold SP, Edwards C. Acarbose. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs. 1988;35(3):214-243. doi: 10.2165/00003495-198835030-00003

 

  1. Moor K, Diard M, Sellin ME, et al. High-avidity IgA protects the intestine by enchaining growing bacteria. Nature. 2017;544(7651):498-502. doi: 10.1038/nature22058

 

  1. FDA U. LivmarliTM (maralixibat): US Prescribing Information. Available from: https://www.fda.gov [Last accessed on 2021 Oct 22].

 

  1. Pharmaceuticals M. Mirum Pharmaceuticals Presents Analyses from its Rare Liver Disease Programs at the EASL International Liver Congress; 2021. Available from: https:// www.mirumpharma.com [Last accessed on 2021 Oct 22].

 

  1. Neimark E, Chen F, Li X, Shneider BL. Bile acid-induced negative feedback regulation of the human ileal bile acid transporter. Hepatology. 2004;40(1):149-156. doi: 10.1002/hep.20295

 

  1. FDA U. Corrected NDA Approval; 2021. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/214662Orig1s000Corrected_ltr.pdf [Last accessed on 2021 Oct 22].

 

  1. Sulkowski MS, Kang M, Matining R, et al. Safety and antiviral activity of the HCV entry inhibitor ITX5061 in treatment-naive HCV-infected adults: A randomized, double-blind, phase 1b study. J Infect Dis. 2014;209(5):658-667. doi: 10.1093/infdis/jit503

 

  1. Huang F, Ning M, Wang K, et al. Discovery of highly polar β-homophenylalanine derivatives as nonsystemic intestine-targeted dipeptidyl peptidase IV inhibitors. J Med Chem. 2019;62(23):10919-10925. doi: 10.1021/acs.jmedchem.9b01649

 

  1. Nitta A, Fujii H, Sakami S, et al. (3R)-3-amino-4-(2,4,5- trifluorophenyl)-N-{4-[6-(2-methoxyethoxy)benzothiazol- 2-yl]tetrahydropyran-4-yl}butanamide as a potent dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Bioorg Med Chem Lett. 2008;18(20):5435-5438. doi: 10.1016/j.bmcl.2008.09.042

 

  1. Fyfe MCT. Chapter One-non-systemic intestine-targeted drugs. In: Lawton G, Witty DR, editors. Progress in Medicinal Chemistry. Netherlands: Elsevier; 2016. p. 1-44.

 

  1. Waring MJ. Lipophilicity in drug discovery. Expert Opin Drug Discov. 2010;5(3):235-248. doi: 10.1517/17460441003605098

 

  1. Forman BM, Goode E, Chen J, et al. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell. 1995;81(5):687-693. doi: 10.1016/0092-8674(95)90530-8

 

  1. Huang W, Ma K, Zhang J, et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science. 2006;312(5771):233-236. doi: 10.1126/science.1121435

 

  1. Zhang Y, Castellani LW, Sinal CJ, Gonzalez FJ, Edwards PA. Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR. Genes Dev. 2004;18(2):157-169. doi: 10.1101/gad.1138104

 

  1. Ma K, Saha PK, Chan L, Moore DD. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest. 2006;116(4):1102-1109. doi: 10.1172/jci25604

 

  1. Wang H, Zhao Z, Zhou J, et al. A novel intestinal-restricted FXR agonist. Bioorg Med Chem Lett. 2017;27(15):3386-3390. doi: 10.1016/j.bmcl.2017.06.003

 

  1. Wang XY, Zhang SY, Li J, Liu HN, Xie X, Nan FJ. Highly lipophilic 3-epi-betulinic acid derivatives as potent and selective TGR5 agonists with improved cellular efficacy. Acta Pharmacol Sin. 2014;35(11):1463-1472. doi: 10.1038/aps.2014.97

 

  1. Maruyama T, Miyamoto Y, Nakamura T, et al. Identification of membrane-type receptor for bile acids (M-BAR). Article. Biochem Biophys Res Commun. 2002;298(5):714-719. doi: 10.1016/s0006-291x(02)02550-0

 

  1. Blaževski J, Petković F, Momčilović M, et al. Betulinic acid regulates generation of neuroinflammatory mediators responsible for tissue destruction in multiple sclerosis in vitro. Acta Pharmacol Sin. 2013;34(3):424-431. doi: 10.1038/aps.2012.181

 

  1. Leber A, Hontecillas R, Zoccoli-Rodriguez V, Bienert C, Chauhan J, Bassaganya-Riera J. Activation of NLRX1 by NX-13 alleviates inflammatory bowel disease through immunometabolic mechanisms in CD4(+) T cells. J Immunol. 2019;203(12):3407-3415. doi: 10.4049/jimmunol.1900364

 

  1. Leber A, Hontecillas R, Zoccoli-Rodriguez V, Ehrich M, Chauhan J, Bassaganya-Riera J. Exploratory studies with NX-13: Oral toxicity and pharmacokinetics in rodents of an orally active, gut-restricted first-in-class therapeutic for IBD that targets NLRX1. Drug Chem Toxicol. 2022;45(1):209-214. doi: 10.1080/01480545.2019.1679828

 

  1. Biopharma L. Landos Biopharma Reports Positive Top-Line Results from NX-13 Phase 1B Trial. Available from: https:// ir.landosbiopharma.com/news-releases/news-release-details/landos-biopharma-reports-positive-top-line-results-nx-13-phase [Last accessed on 2022 Nov 27].

 

  1. Griffett K, Solt LA, El-Gendy Bel D, Kamenecka TM, Burris TP. A liver-selective LXR inverse agonist that suppresses hepatic steatosis. ACS Chem Biol. 2013;8(3):559-567. doi: 10.1021/cb300541g

 

  1. Flaveny CA, Griffett K, El-Gendy Bel D, et al. Broad anti-tumor activity of a small molecule that selectively targets the warburg effect and lipogenesis. Cancer Cell. 2015;28(1):42-56. doi: 10.1016/j.ccell.2015.05.007

 

  1. Zelcer N, Hong C, Boyadjian R, Tontonoz P. LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science. 2009;325(5936):100-104. doi: 10.1126/science.1168974

 

  1. Zuercher WJ, Buckholz RG, Campobasso N, et al. Discovery of tertiary sulfonamides as potent liver X receptor antagonists. J Med Chem. 2010;53(8):3412-3416. doi: 10.1021/jm901797p

 

  1. Friend DR, Chang GW. A colon-specific drug-delivery system based on drug glycosides and the glycosidases of colonic bacteria. J Med Chem. 1984;27(3):261-266. doi: 10.1021/jm00369a005

 

  1. Di L, Kerns EH, Carter GT. Drug-like property concepts in pharmaceutical design. Curr Pharm Des. 2009;15(19):2184-2194. doi: 10.2174/138161209788682479

 

  1. Bodor N, Buchwald P. Soft drug design: General principles and recent applications. Med Res Rev. 2000;20(1):58-101. doi: 10.1002/(sici)1098-1128(200001)20:1<58:Aid-med3>3.0.Co;2-x

 

  1. Robinson RP, Bartlett JA, Bertinato P, et al. Discovery of microsomal triglyceride transfer protein (MTP) inhibitors with potential for decreased active metabolite load compared to dirlotapide. Bioorg Med Chem Lett. 2011;21(14):4150-4154. doi: 10.1016/j.bmcl.2011.05.099

 

  1. Wetterau JR, Aggerbeck LP, Laplaud PM, McLean LR. Structural properties of the microsomal triglyceride-transfer protein complex. Biochemistry. 2002;30(18):4406-4412. doi: 10.1021/bi00232a006

 

  1. Wren JA, Gossellin J, Sunderland SJ. Dirlotapide: A review of its properties and role in the management of obesity in dogs. J Vet Pharmacol Ther. 2007;30 Suppl 1:11-16. doi: 10.1111/j.1365-2885.2007.00864.x

 

  1. Belvisi MG, Hele DJ. Soft steroids: A new approach to the treatment of inflammatory airways diseases. Pulm Pharmacol Ther. 2003;16(6):321-325. doi: 10.1016/S1094-5539(03)00105-6

 

  1. Bodor N, Murakami T, Wu WM. Soft drugs. 18. Oral and rectal delivery of loteprednol etabonate, a novel soft corticosteroid, in rats--for safer treatment of gastrointestinal inflammation. Pharm Res. 1995;12(6):869-874. doi: 10.1023/a:1016213121069

 

  1. Laufer SA, Margutti S, Fritz MD. Substituted isoxazoles as potent inhibitors of p38 MAP kinase. ChemMedChem. 2006;1(2):197-207. doi: 10.1002/cmdc.200500025

 

  1. Hasumi K, Sato S, Saito T, et al. Design and synthesis of 5-[(2-chloro-6-fluorophenyl)acetylamino]-3-(4- fluorophenyl)-4-(4-pyrimidinyl)isoxazole (AKP-001), a novel inhibitor of p38 MAP kinase with reduced side effects based on the antedrug concept. Bioorg Med Chem. 2014;22(15):4162-4176. doi: 10.1016/j.bmc.2014.05.045

 

  1. Goldstein DM, Kuglstatter A, Lou Y, Soth MJ. Selective p38α inhibitors clinically evaluated for the treatment of chronic inflammatory disorders. J Med Chem. 2009;53(6):2345-2353. doi: 10.1021/jm9012906

 

  1. Han FH, Ning MM, Cao H, et al. Design of G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) soft drugs with reduced gallbladder-filling effects. Eur J Med Chem. 2020;203:112619. doi: 10.1016/j.ejmech.2020.112619

 

  1. Shim S, Krishnaiah M, Sankham MR, et al. Discovery of (E)-3-(3-((2-Cyano-4’-dimethylaminobiphenyl-4- ylmethyl)cyclohexanecarbonylamino)-5-fluorophenyl) acrylic acid methyl ester, an intestine-specific, FXR partial agonist for the treatment of nonalcoholic steatohepatitis. J Med Chem. 2022;65(14):9974-10000. doi: 10.1021/acs.jmedchem.2c00641

 

  1. Jiang L, Zhang H, Xiao D, Wei H, Chen Y. Farnesoid X receptor (FXR): Structures and ligands. Comput Struct Biotechnol J. 2021;19:2148-2159. doi: 10.1016/j.csbj.2021.04.029

 

  1. Albert A. Chemical aspects of selective toxicity. Nature. 1958;182(4633):421-423. doi: 10.1038/182421a0

 

  1. Rautio J, Kumpulainen H, Heimbach T, et al. Prodrugs: Design and clinical applications. Nat Rev Drug Discov. 2008;7(3):255-270. doi: 10.1038/nrd2468

 

  1. Huttunen KM, Raunio H, Rautio J. Prodrugs-- from serendipity to rational design. Pharmacol Rev. 2011;63(3):750-771. doi: 10.1124/pr.110.003459

 

  1. Egan LJ, Sandborn WJ. Drug therapy of inflammatory bowel disease. Drugs Today (Barc). 1998;34(5):431-446. doi: 10.1358/dot.1998.34.5.485242

 

  1. Jeong S, Lee H, Kim S, et al. 5-Aminosalicylic acid azo-coupled with a GPR109A agonist is a colon-targeted anticolitic codrug with a reduced risk of skin toxicity. Mol Pharm. 2020;17(1):167-179. doi: 10.1021/acs.molpharmaceut.9b00872

 

  1. Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer RJ. Review article: The role of butyrate on colonic function. Aliment Pharmacol Ther. 2007;27(2):104-119. doi: 10.1111/j.1365-2036.2007.03562.x

 

  1. Graff EC, Fang H, Wanders D, Judd RL. Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2. Metabolism. 2016;65(2):102-113. doi: 10.1016/j.metabol.2015.10.001

 

  1. Hanson J, Gille A, Zwykiel S, et al. Nicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2- dependent prostanoid formation in mice. J Clin Invest. 2010;120(8):2910-2919. doi: 10.1172/Jci42273

 

  1. Zhao JX, Zhang B, Mao Q, et al. Discovery of a colon-targeted azo prodrug of tofacitinib through the establishment of colon-specific delivery systems constructed by 5-ASA-PABA-MAC and 5-ASA-PABA-diamine for the treatment of ulcerative colitis. J Med Chem. 2022;65(6):4926-4948. doi: 10.1021/acs.jmedchem.1c02166

 

  1. Cannemeyer W, Thompson JR, Lichtenstein MR. Severe para-aminosalicylic acid hypersensitivity. Blood. 1955;10(1):62-75. doi: 10.1182/blood.V10.1.62.62

 

  1. Gisbert JP, Gomollon F, Mate J, Pajares JM. Role of 5-aminosalicylic acid (5-ASA) in treatment of inflammatory bowel disease: A systematic review. Dig Dis Sci. 2002;47(3):471-488. doi: 10.1023/a:1017987229718

 

  1. Beeken W, Howard D, Bigelow J, et al. Controlled trial of 4-ASA in ulcerative colitis. Dig Dis Sci. 1997;42(2):354-358. doi: 10.1023/a:1018874120749

 

  1. Vadnerkar G, Dhaneshwar S. Macromolecular prodrug of 4-aminosalicylic acid for targeted delivery to inflamed colon. Curr Drug Discov Technol. 2013;10(1):16-24.

 

  1. Lee H, Park S, Ju S, et al. Preparation and evaluation of colon-targeted prodrugs of the microbial metabolite 3-indolepropionic acid as an anticolitic agent. Mol Pharmaceut. 2021;18(4):1730-1741. doi: 10.1021/acs.molpharmaceut.0c01228

 

  1. Lee JS, Jung YJ, Kim YM. Synthesis and evaluation of N-acyl-2- (5-fluorouracil-1-yl)-D,L-glycine as a colon-specific prodrug of 5-fluorouracil. J Pharm Sci. 2001;90(11):1787-1794. doi: 10.1002/jps.1128

 

  1. Diasio RB, Harris BE. Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet. 1989;16(4):215-237. doi: 10.2165/00003088-198916040-00002

 

  1. Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem. 1993;62:385-427. doi: 10.1146/annurev.bi.62.070193.002125

 

  1. Aniceto N, Freitas AA, Bender A, Ghafourian T. Simultaneous prediction of four ATP-binding cassette transporters’ substrates using multi-label QSAR. Mol Inform. 2016;35(10):514-528. doi: 10.1002/minf.201600036

 

  1. Chitraju C, Walther TC, Farese RV Jr. The triglyceride synthesis enzymes DGAT1 and DGAT2 have distinct and overlapping functions in adipocytes. J Lipid Res. 2019;60(6):1112-1120. doi: 10.1194/jlr.M093112

 

  1. Serrano-Wu MH, Coppola GM, Gong Y, et al. Intestinally targeted diacylglycerol acyltransferase 1 (DGAT1) inhibitors robustly suppress postprandial triglycerides. ACS Med Chem Lett. 2012;3(5):411-415. doi: 10.1021/ml3000512

 

  1. Sachdev V, Leopold C, Bauer R, et al. Novel role of a triglyceride-synthesizing enzyme: DGAT1 at the crossroad between triglyceride and cholesterol metabolism. Biochim Biophys Acta. 2016;1861(9 Pt A):1132-1141. doi: 10.1016/j.bbalip.2016.06.014

 

  1. de la Rosa Rodriguez MA, Deng L, Gemmink A, et al. Hypoxia-inducible lipid droplet-associated induces DGAT1 and promotes lipid storage in hepatocytes. Mol Metab. 2021;47:101168. doi: 10.1016/j.molmet.2021.101168

 

  1. Sandborn WJ, Hanauer SB. Systematic review: The pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro-drugs used in the management of ulcerative colitis. Aliment Pharmacol Ther. 2003;17(1):29-42. doi: 10.1046/j.1365-2036.2003.01408.x

 

  1. Dahan A, Amidon GL. Small intestinal efflux mediated by MRP2 and BCRP shifts sulfasalazine intestinal permeability from high to low, enabling its colonic targeting. Am J Physiol Gastrointest Liver Physiol. 2009;297(2):G371-G377. doi: 10.1152/ajpgi.00102.2009

 

  1. Thomas C, Auwerx J, Schoonjans K. Bile acids and the membrane bile acid receptor TGR5--connecting nutrition and metabolism. Thyroid. 2008;18(2):167-174. doi: 10.1089/thy.2007.0255

 

  1. Chu ZL, Carroll C, Alfonso J, et al. A role for intestinal endocrine cell-expressed g protein-coupled receptor 119 in glycemic control by enhancing glucagon-like Peptide-1 and glucose-dependent insulinotropic Peptide release. Endocrinology. 2008;149(5):2038-2047. doi: 10.1210/en.2007-0966

 

  1. Keitel V, Droge C, Haussinger D. Targeting FXR in cholestasis. Handb Exp Pharmacol. 2019;256:299-324. doi: 10.1007/164_2019_231

 

  1. Knipp GT, Ho NF, Barsuhn CL, Borchardt RT. Paracellular diffusion in Caco-2 cell monolayers: Effect of perturbation on the transport of hydrophilic compounds that vary in charge and size. J Pharm Sci. 1997;86(10):1105-1110. doi: 10.1021/js9700309

 

Share
Back to top
Gene & Protein in Disease, Electronic ISSN: 2811-003X Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept