4,8-Dimethylcoumarin Inhibitors of Intestinal Anion Exchanger Slc26a3 (Downregulated in Adenoma) for Anti-Absorptive Therapy of Constipation

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2019 Aug 8

PMID 31389695

Citations 11

Authors

Sujin Lee

Onur Cil

Peter M Haggie

Alan S Verkman

Affiliations

Soon will be listed here.

Abstract

The chloride/bicarbonate exchanger SLC26A3 (downregulated in adenoma) is expressed mainly in colonic epithelium, where it dehydrates the stool by facilitating the final step of chloride and fluid absorption. SLC26A3 inhibition has predicted efficacy in various types of constipation including that associated with cystic fibrosis. We previously identified, by high-throughput screening, 4,8-dimethylcoumarin inhibitors of murine slc26a3 with IC down to ∼150 nM. Here, we synthesized a focused library of forty-three 4,8-dimethylcoumarin analogues. Structure-activity studies revealed the requirement of 4,8-dimethylcoumarin-3-acetic acid for activity. The most potent inhibitors were produced by replacements at C7, including 3-iodo- () and 3-trifluoromethyl- (), with IC of 40 and 25 nM, respectively. Pharmacokinetics in mice showed predicted therapeutic concentrations of for >72 h following a single 10 mg/kg oral dose. at 10 mg/kg fully normalized stool water content in a loperamide-induced mouse model of constipation. The favorable inhibition potency, selectivity within the SLC26 family, and pharmacological properties of support its further preclinical development.

Citing Articles

DRA involvement in linaclotide-stimulated bicarbonate secretion during loss of CFTR function.

Sarthi J, Trumbull A, Abazari S, van Unen V, Chan J, Jiang Y JCI Insight. 2024; 9(14).

PMID: 38869953 PMC: 11383163. DOI: 10.1172/jci.insight.172364.

Substituted 4-methylcoumarin inhibitors of SLC26A3 (DRA) for treatment of constipation and hyperoxaluria.

Ahmadi M, de Souza Goncalves L, Verkman A, Cil O, Anderson M RSC Med Chem. 2024; 15(5):1731-1736.

PMID: 38784456 PMC: 11110725. DOI: 10.1039/d3md00644a.

Selective isoxazolopyrimidine PAT1 (SLC26A6) inhibitors for therapy of intestinal disorders.

Chu T, Karmakar J, Haggie P, Tan J, Master R, Ramaswamy K RSC Med Chem. 2023; 14(11):2342-2347.

PMID: 37974969 PMC: 10650448. DOI: 10.1039/d3md00302g.

SLC26 Anion Transporters.

Geertsma E, Oliver D Handb Exp Pharmacol. 2023; 283:319-360.

PMID: 37947907 DOI: 10.1007/164_2023_698.

Key role of down-regulated in adenoma () chloride/bicarbonate exchanger in linaclotide-stimulated intestinal bicarbonate secretion upon loss of CFTR function.

Sarthi J, Trumbull A, Abazari S, van Unen V, Chan J, Jiang Y bioRxiv. 2023; .

PMID: 37205513 PMC: 10187319. DOI: 10.1101/2023.05.05.539132.

References

Byeon M, Westerman M, Maroulakou I, Henderson K, Suster S, Zhang X . The down-regulated in adenoma (DRA) gene encodes an intestine-specific membrane glycoprotein. Oncogene. 1996; 12(2):387-96. View

Walker N, Simpson J, Yen P, Gill R, Rigsby E, Brazill J . Down-regulated in adenoma Cl/HCO3 exchanger couples with Na/H exchanger 3 for NaCl absorption in murine small intestine. Gastroenterology. 2008; 135(5):1645-1653.e3. PMC: 2673535. DOI: 10.1053/j.gastro.2008.07.083. View

Ferroud D, Collard J, Klich M, Mauvais P, Lassaigne P, Bonnefoy A . Synthesis and biological evaluation of coumarincarboxylic acids as inhibitors of gyrase B. L-rhamnose as an effective substitute for L-noviose. Bioorg Med Chem Lett. 1999; 9(19):2881-6. DOI: 10.1016/s0960-894x(99)00493-x. View

Kontogiorgis C, Detsi A, Hadjipavlou-Litina D . Coumarin-based drugs: a patent review (2008 -- present). Expert Opin Ther Pat. 2012; 22(4):437-54. DOI: 10.1517/13543776.2012.678835. View

Gebauer M . Synthesis and structure-activity relationships of novel warfarin derivatives. Bioorg Med Chem. 2007; 15(6):2414-20. DOI: 10.1016/j.bmc.2007.01.014. View

Mladenovic M, Patsilinakos A, Pirolli A, Sabatino M, Ragno R . Understanding the Molecular Determinant of Reversible Human Monoamine Oxidase B Inhibitors Containing 2H-Chromen-2-One Core: Structure-Based and Ligand-Based Derived Three-Dimensional Quantitative Structure-Activity Relationships Predictive Models. J Chem Inf Model. 2017; 57(4):787-814. DOI: 10.1021/acs.jcim.6b00608. View

Bharucha A, Wouters M, Tack J . Existing and emerging therapies for managing constipation and diarrhea. Curr Opin Pharmacol. 2017; 37:158-166. PMC: 5725238. DOI: 10.1016/j.coph.2017.10.015. View

Rao S, Rattanakovit K, Patcharatrakul T . Diagnosis and management of chronic constipation in adults. Nat Rev Gastroenterol Hepatol. 2016; 13(5):295-305. DOI: 10.1038/nrgastro.2016.53. View

Haggie P, Cil O, Lee S, Tan J, Rivera A, Phuan P . SLC26A3 inhibitor identified in small molecule screen blocks colonic fluid absorption and reduces constipation. JCI Insight. 2018; 3(14). PMC: 6124422. DOI: 10.1172/jci.insight.121370. View

10.

Sabharwal S . Gastrointestinal Manifestations of Cystic Fibrosis. Gastroenterol Hepatol (N Y). 2016; 12(1):43-7. PMC: 4865785. View

11.

Cil O, Phuan P, Lee S, Tan J, Haggie P, Levin M . CFTR activator increases intestinal fluid secretion and normalizes stool output in a mouse model of constipation. Cell Mol Gastroenterol Hepatol. 2016; 2(3):317-327. PMC: 4844355. DOI: 10.1016/j.jcmgh.2015.12.010. View

12.

Marzaro G, Guiotto A, Borgatti M, Finotti A, Gambari R, Breveglieri G . Psoralen derivatives as inhibitors of NF-κB/DNA interaction: synthesis, molecular modeling, 3D-QSAR, and biological evaluation. J Med Chem. 2013; 56(5):1830-42. DOI: 10.1021/jm3009647. View

13.

Camilleri M, Ford A, Mawe G, Dinning P, Rao S, Chey W . Chronic constipation. Nat Rev Dis Primers. 2017; 3:17095. DOI: 10.1038/nrdp.2017.95. View

14.

Borgatti M, Chilin A, Piccagli L, Lampronti I, Bianchi N, Mancini I . Development of a novel furocoumarin derivative inhibiting NF-κB dependent biological functions: design, synthesis and biological effects. Eur J Med Chem. 2011; 46(10):4870-7. DOI: 10.1016/j.ejmech.2011.07.032. View

15.

Marzaro G, Lampronti I, Borgatti M, Manzini P, Gambari R, Chilin A . Psoralen derivatives as inhibitors of NF-κB interaction: the critical role of the furan ring. Mol Divers. 2015; 19(3):551-61. DOI: 10.1007/s11030-015-9586-2. View

16.

Matano L, Morris H, Hesser A, Martin S, Lee W, Owens T . Antibiotic That Inhibits the ATPase Activity of an ATP-Binding Cassette Transporter by Binding to a Remote Extracellular Site. J Am Chem Soc. 2017; 139(31):10597-10600. PMC: 5699463. DOI: 10.1021/jacs.7b04726. View

17.

Li B, Pai R, Di M, Aiello D, Barnes M, Butler M . Coumarin-based inhibitors of Bacillus anthracis and Staphylococcus aureus replicative DNA helicase: chemical optimization, biological evaluation, and antibacterial activities. J Med Chem. 2012; 55(24):10896-908. PMC: 3531573. DOI: 10.1021/jm300922h. View

18.

Hoglund P, Haila S, Socha J, TOMASZEWSKI L, Saarialho-Kere U, Karjalainen-Lindsberg M . Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea. Nat Genet. 1996; 14(3):316-9. DOI: 10.1038/ng1196-316. View

19.

Lipinski C, Lombardo F, Dominy B, Feeney P . Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001; 46(1-3):3-26. DOI: 10.1016/s0169-409x(00)00129-0. View

20.

Galligan J, Sternini C . Insights into the Role of Opioid Receptors in the GI Tract: Experimental Evidence and Therapeutic Relevance. Handb Exp Pharmacol. 2017; 239:363-378. PMC: 6310692. DOI: 10.1007/164_2016_116. View