Subcutaneous Administration of an ASBT Inhibitor

Abstract

The present invention relates to an apical sodium-dependent bile acid transporter (ASBT) inhibitor for use in the treatment of liver or kidney diseases or disorders, which is administered subcutaneously. Such administration also targets ASBT in the kidney and can thus be useful for the treatment of liver or kidney diseases and conditions that require more potent inhibition of bile acid circulation, for example, in the treatment of biliary obstruction, or cholestatic liver diseases and conditions including disorders or defects in bile flow.

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority to Swedish Patent Application No. 2250486 - 4, filed on April 22, 2022, the disclosure of which is hereby incorporated by reference in its entirety.

[0002] The present invention relates to apical sodium - dependent bile acid transporter (ASBT) inhibitors for use in the treatment of liver or kidney diseases or disorders, which are administered subcutaneously. Such administration also targets ASBT in the kidney and can thus be useful in the treatment of liver and kidney diseases and conditions that require more potent inhibition of bile acid circulation, for example, in the treatment of biliary obstruction, or cholestatic liver diseases and conditions including disorders or defects in bile flow.

Background Art

[0003] Liver diseases include a number of different diseases, which can be caused by various factors including viral infections (such as hepatitis); obesity, and alcohol abuse; genetic defects; abnormalities of the immune system (e.g., causing primary biliary cholangitis, primary sclerosing cholangitis and autoimmune hepatitis); and various cancers. If left untreated, liver diseases can cause severe damage to the liver (e.g., cirrhosis) and ultimately lead to liver failure.

[0004] In several liver diseases, bile acids are involved in disease progression. Bile acids are physiological surfactants that play important roles in the intestinal absorption and transport of lipids, nutrients, and vitamins. They are also signaling molecules that activate nuclear and membrane-bound receptors, as well as cellular signaling pathways that regulate lipid, glucose, and energy metabolism. Bile acids are steroid acids synthesized from cholesterol in the liver and stored in the gallbladder as mixed micelles. During digestion, the duodenum induces the release of hormones that cause the gallbladder to contract, thereby releasing bile acids into the small intestine, where they enable the absorption of fat-soluble vitamins and cholesterol. When bile acids reach the ileum, they are reabsorbed from the intestine, secreted into the portal blood, and returned to the liver via the portal circulation. In this way, more than 90% of bile acids are recycled and returned to the liver. These bile acids are then transported across the sinusoidal cell membrane of hepatocytes and resecreted into bile across the canalicular membrane. During this first pass, 75-90% of bile acids are taken up by hepatocytes, completing one enterohepatic circulation. A portion of the bile acids not removed by the liver enters the systemic circulation, where free bile acids are filtered by the renal glomeruli, efficiently reabsorbed in the proximal renal tubules, and returned to the systemic circulation. Interestingly, most of the bile acids secreted into bile across the canalicular membrane are derived from the recycling pool, and less than 10% arise from de novo hepatic synthesis. The small amount of bile acids not reabsorbed in the ileum reaches the colon. In the intestinal lumen, primary bile acids (cholic acid and chenodeoxycholic acid) are converted to secondary bile acids (deoxycholic acid and lithocholic acid) mainly by mono- or di-dehydroxylation reactions of the steroid nucleus under the action of intestinal bacteria. Bile acids not absorbed by the intestine are then excreted in feces.

[0005] The transport of bile acids (enterohepatic circulation) in the human body is mediated by the action of members of the SLC10 family of solute transporter proteins, particularly the Na expressed on the sinusoidal cell membrane of hepatocytes +-It is regulated by the sodium taurocholate cotransporting polypeptide (NTCP, also called liver bile acid transporter (LBAT); gene symbol SLC10A1), and the apical sodium-dependent bile acid transporter (ASBT, ISBT, ABAT or NTCP2; gene symbol SLC10A2) expressed in the apical membranes of ileal enterocytes, proximal tubular cells, bile duct epithelium, large bile duct cells and gallbladder epithelial cells. In the liver, bile acids are efficiently extracted from portal blood by the liver bile acid transporter (LBAT) and resecreted across the canalicular membrane by the bile salt export pump (BSEP; gene symbol ABCB11). The reabsorption of bile acids in the ileum is handled by the apical sodium-dependent bile acid transporter (ASBT), generally called the ileal bile acid transporter (IBAT) in the ileum. Both LBAT and ASBT function as electrogenic sodium-solute cotransporters that move more than two Na + ions per molecule of solute.

[0006] Overall, the efficient transport system helps maintain a constant bile acid pool, thereby ensuring a sufficiently high level of conjugated bile acids in the intestine to promote lipid absorption and reduce the bacterial load in the small intestine. This system also protects the intestinal and hepatobiliary compartments by minimizing bile acid losses in feces and urine and eliminating potentially cytotoxic surfactants (as outlined by Kosters and Karpen (Xenobiotica 2008, Vol. 38, pp. 1043 - 1071); Chiang (J. Lipid Res. 2009, Vol. 50, pp. 1955 - 1966); and Dawson (Handb. Exp. Pharmacol. 2011, Vol. 201, pp. 169 - 203)).

[0007] The regulation of the size of the bile acid pool by converting cholesterol to bile acids in the liver has been found to play an important role in cholesterol homeostasis, which corresponds to the major route for excreting cholesterol from the body. The liver plays an essential role in removing endogenous and xenobiotic compounds from the body. Normal hepatic bile secretion and enterohepatic circulation are required to excrete endogenous compounds such as cholesterol and bilirubin and their metabolites from the body, thereby maintaining lipid and bile acid homeostasis. (Kosters and Karpen, Xenobiotica 2008, Vol. 38, pp. 1043 - 1071).

[0008] For various reasons, bile flow from the liver to the duodenum can be impaired or blocked, thereby causing cholestasis, which leads to the accumulation of bile acids in the liver. Cholestasis can occur within the liver (intrahepatic cholestasis) or can be caused by obstruction in the bile ducts, such as gallstones, cysts, and tumors that restrict bile flow (extrahepatic or obstructive cholestasis). Cholestasis can lead to a rapid increase in serum bile acid levels and can cause jaundice and pruritus.

[0009] A number of compounds that can inhibit the reabsorption of bile acids in the ileum (i.e., ASBT or IBAT inhibitors) have been discovered over the past few decades; see, for example, WO 97 / 33882, WO 02 / 50051, WO 03 / 022286, WO 2008 / 058628, WO 2011 / 137135, and WO 2019 / 234077. Most of these compounds are not systemically absorbed after oral administration. ASBT inhibitor compounds were initially intended for the treatment of dyslipidemic metabolic disorders and gastrointestinal diseases (such as constipation; see, for example, WO 2004 / 089350), while it was later discovered that ASBT inhibitors can also be used for the treatment of liver diseases; see, for example, WO 2012 / 064266, WO 2013 / 063512, and EP 1535913. Two ASBT inhibitors, namely, PFIC, and Bylvay™ (odevixibat) for the treatment of pruritus in PFIC, and Livmarli™ (maralixibat) for the treatment of pruritus in Alagille syndrome, have recently been approved for the treatment of cholestatic liver diseases.

Prior Art Documents

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Summary of the Invention

[0012] The treatment of these and other liver and kidney diseases with ASBT inhibitors is currently under development. However, despite recent developments in this field and the gradually increasing number of approved drugs, the treatment of liver diseases, particularly more severe forms of cholestatic liver diseases, remains a challenge. For these conditions, inhibition of bile acid reabsorption in the ileum alone may not be sufficient to provide effective treatment. Therefore, there is a continuing need for improvement in the treatment of liver diseases.

Brief Description of the Drawings

[0013]

Figure 1

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Mode for Carrying Out the Invention

[0014] In a first aspect, provided herein is an ASBT inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of a liver or kidney disease or disorder, wherein the ASBT inhibitor is administered subcutaneously. It has been found that subcutaneous administration of an ASBT inhibitor such as elobixibat results in a constant exposure that persists for more than 24 hours and provides high bioavailability of the ASBT inhibitor. This is surprising because intravenous administration of the same ASBT inhibitor has been found to result in rapid clearance of the compound (see Figure 1).

[0015] Since ASBT is mainly expressed in the ileum (often called IBAT in the ileum), ASBT inhibitors do not need to be systemically absorbed for most indications. In fact, the systemic absorption of most known ASBT inhibitors is very low, for example less than 10%. However, since ASBT is also expressed in proximal tubule cells of the kidney, systemically absorbed ASBT inhibitors may also inhibit the reuptake of bile acids in the kidney. This may increase the bile acid level in urine and the removal of bile acids from the body via urine. Therefore, it is predicted that a systemically absorbed ASBT inhibitor that acts on both the ileum and the kidney will lead to a greater reduction in bile acid levels than a non-systemically absorbed ASBT inhibitor that acts only on the ileum. Under obstructive conditions where bile flow is completely blocked (e.g., due to gallstones, tumors, or inflammation), ASBT inhibitors acting on the ileum may not provide benefits because the amount of bile acid blocked in the ileum is very limited. In contrast, targeting renal ASBT can be an alternative means to increase bile acid excretion and reduce the bile acid load in the liver. Therefore, subcutaneous administration of an ASBT inhibitor may result in a bile acid-regulating effect that likely persists longer than oral administration of the ASBT inhibitor under obstructive conditions. Such an effect can be useful in the treatment of liver and kidney diseases that require more potent inhibition of bile acid circulation or when oral administration may not provide benefits (i.e., when bile flow is blocked).

[0016] ASBT inhibitor In some embodiments, the ASBT inhibitor for use in the present invention does not inhibit renal ASBT at clinically relevant levels after oral administration of the ASBT inhibitor.

[0017] In some embodiments, the systemic absorption of such an ASBT inhibitor after oral administration is less than 10%, such as less than 9%, such as less than 8%, such as less than 7%, or such as less than 6%. In some embodiments, the systemic absorption of such an ASBT inhibitor after oral administration is less than 5%. In some embodiments, the systemic absorption of such an ASBT inhibitor after oral administration is less than 1%.

[0018] In some embodiments, the ASBT inhibitor is a compound disclosed in, for example, WO 93 / 16055, WO 94 / 18183, WO 94 / 18184, WO 96 / 05188, WO 96 / 08484, WO 96 / 16051, WO 97 / 33882, WO 98 / 03818, WO 98 / 07449, WO 98 / 40375, WO 99 / 35135, WO 99 / 64409, WO 99 / 64410, WO 00 / 01687, WO 00 / 47568, WO 00 / 61568, WO 00 / 38725, WO 00 / 38726, WO 00 / 38727, WO 00 / 38728, WO 00 / 38729, WO 01 / 66533, WO 01 / 68096, WO 02 / 32428, WO 02 / 50051, WO 03 / 020710, WO 03 / 022286, WO 03 / 022825, WO 03 / 022830, WO 03 / 061663, WO 03 / 091232, WO 03 / 106482, WO 2004 / 006899, WO 2004 / 076430, WO 2007 / 009655, WO 2007 / 009656, WO 2008 / 058628, WO 2008 / 058630, WO 2011 / 137135, WO 2019 / 234077, WO 2020 / 161216, WO 2020 / 161217, WO 2021 / 110884, WO 2021 / 110885, WO 2021 / 110886, WO 2021 / 110887, WO 2022 / 029101, DE 19825804, EP 864582, EP 489423, EP 549967, EP 573848, EP 624593, EP 624594, EP 624595, EP 624596, EP 0864582, EP 1173205, EP 1535913, EP 1719768 or EP 3210977.

[0019] In some embodiments, the ASBT inhibitor is a compound of formula (I):

[0020]

Chemical formula

[0021] (wherein, R v is selected from hydrogen or C 1~6 alkyl; R 1 and R 2 one of which is selected from hydrogen, C 1~6 alkyl or C 2~6 alkenyl, and the other is selected from C 1~6 alkyl or C 2~6 alkenyl; R x and R y are independently selected from the group consisting of hydrogen, hydroxy, amino, mercapto, C 1~6 alkyl, C 1~6 alkoxy, N-(C 1~6 alkyl)amino, N,N-(C 1~6 alkyl) 2 amino, C where a is 0 to 2 1~6 alkylS(O) a ; M is selected from -N- or -CH-; R z is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6 alkanoyl, C 1~6 alkanoyloxy, N-(C 1~6 alkyl)amino, N,N-(C 1~6 alkyl) 2 amino, C 1~6 alkanoylamino, N-(C 1~6 alkyl)carbamoyl, N,N-(C 1~6 alkyl) 2 carbamoyl, C where a is 0 to 2 1~6 alkylS(O) a , C 1~6 alkoxycarbonyl, N-(C 1~6 alkyl)sulfamoyl and N,N-(C 1~6 alkyl) 2 sulfamoyl; v is from 0 to 5; R 4 and R 5 one of which is a group of formula (IA):

[0022]

Chemical formula

[0023] and R 3 and R 6 , and R 4 and R 5 the other is independently hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1~4 alkyl, C 2~4 alkenyl, C 2~4 alkynyl, C 1~4 alkoxy, C 1~4 alkanoyl, C 1~4 alkanoyloxy, N-(C 1~4 alkyl)amino, N,N-(C 1~4 alkyl) 2 amino, C 1~4 alkanoylamino, N-(C 1~4 alkyl)carbamoyl, N,N-(C 1~4 alkyl) 2 carbamoyl, C where a is from 0 to 2 1~4 alkylS(O) a , C 1~4 alkoxycarbonyl, N-(C 1~4 alkyl)sulfamoyl and N,N-(C 1~4 alkyl) 2 sulfamoyl, selected from the group consisting of; where R 3 and R 6 , and R 4 and R 5 the other may optionally be substituted by one or more R 16 on carbon; X is -O-, -N(R a ), -S(O) b - or -CH(R a )-; where R ais hydrogen or C 1~6 alkyl, and b is from 0 to 2; Ring A is aryl or heteroaryl; wherein ring A is optionally substituted by one or more substituents selected from R 17 ; R 7 is hydrogen, C 1~4 alkyl, carbocyclic or heterocyclic; wherein R 7 is optionally substituted by one or more substituents selected from R 18 ; R 8 is hydrogen or C 1~4 alkyl; R 9 is hydrogen or C 1~4 alkyl; R 10 is hydrogen, C 1~4 alkyl, carbocyclic or heterocyclic; wherein R 10 is optionally substituted by one or more substituents selected from R 19 ; R 11 is carboxy, sulfo, sulfino, phosphono, -P(O)(OR c )(OR d ), -P(O)(OH)(OR c ), -P(O)(OH)(R d ) or -P(O)(OR c )(R d ), wherein R c and R d are independently selected from C 1~6 alkyl; or R 11 is a group of formula (IB) or (IC):

[0024]

Chemical formula

[0025] (wherein, Y is -N(R n )-, -N(Rn ) C(O)-, -N(R n ) C(O)(CR s R t ) v N(R n ) C(O)-, -O-, and -S(O)a-; where a is 0 to 2, v is 1 to 2, R s and R t are independently selected from hydrogen or C 26 alkyl optionally substituted by R 1~4 ; R n is hydrogen or C 1~4 alkyl; R 12 is hydrogen or C 1~4 alkyl; R 13 and R 14 are independently selected from hydrogen, C 1~6 alkyl, carbocyclic, or heterocyclic; when q is 0, R 14 may further be selected from hydroxy; where R 13 and R 14 are independently optionally substituted by one or more substituents selected from R 20 ; R 15 is carboxy, sulfo, sulfino, phosphono, -P(O)(OR e )(OR f ), -P(O)(OH)(OR e ), -P(O)(OH)(R e ), or -P(O)(OR e )(R f ); where R e and R f are independently selected from C 1~6 alkyl; p is 1 to 3; where the values of R 13 may be the same or different; q is 0 to 1; r is 0 to 3; where the values of R 14 may be the same or different) and m is from 0 to 2; where R 10 may have the same or different values; n is from 1 to 3; where R 7 may have the same or different values; Ring B is a nitrogen-linked heterocyclyl substituted by one group selected from R 23 and may be further optionally substituted by one or more R 24 on carbon; where when the nitrogen-linked heterocyclyl contains an -NH- moiety, the nitrogen thereof may be optionally substituted by a group selected from R 25 ; R 16 、R 17 and R 18 are independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1~4 alkyl, C 2~4 alkenyl, C 2~4 alkynyl, C 1~4 alkoxy, C 1~4 alkanoyl, C 1~4 alkanoyloxy, N-(C 1~4 alkyl)amino, N,N-(C 1~4 alkyl) 2 amino, C 1~4 alkanoylamino, N-(C 1~4 alkyl)carbamoyl, N,N-(C 1~4 alkyl) 2 carbamoyl, C where a is from 0 to 2 1~4 alkylS(O) a 、C 1~4 alkoxycarbonyl, N-(C 1~4 alkyl)sulfamoyl and N,N-(C 1~4 alkyl) 2 sulfamoyl, selected from the group consisting of; where R 16 、R 17 and R 18 may be optionally substituted by one or more R 21 on carbon; R 19 、R20 , R 24 and R 26 are each independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1~4 alkyl, C 2~4 alkenyl, C 2~4 alkynyl, C 1~4 alkoxy, C 1~4 alkanoyl, C 1~4 alkanoyloxy, N-(C 1~4 alkyl)amino, N,N-(C 1~4 alkyl) 2 amino, C 1~4 alkanoylamino, N-(C 1~4 alkyl)carbamoyl, N,N-(C 1~4 alkyl) 2 carbamoyl, C where a is 0 - 2 1~4 alkylS(O) a , C 1~4 alkoxycarbonyl, N-(C 1~4 alkyl)sulfamoyl, N,N-(C 1~4 alkyl) 2 sulfamoyl, carbocyclic, heterocyclic, benzyloxycarbonylamino, (C 1~4 alkyl) 3 silyl, sulfo, sulfino, amidino, phosphono, -P(O)(OR a )(OR b ), -P(O)(OH)(OR a ), -P(O)(OH)(R a ), or -P(O)(OR a )(R b ), and where R a and R b are each independently selected from C 1~6 alkyl; and where R 19 , R 20 , R 24 and R 26 may each independently be optionally substituted on carbon by one or more R 22 ; R 21 and R 22is independently selected from the group consisting of halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamide, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N,N-dimethylsulfamoyl; R 23 is carboxy, sulfo, sulfino, phosphono, -P(O)(OR g )(OR h ), -P(O)(OH)(OR g ), -P(O)(OH)(R g ) or -P(O)(OR g )(R h ), where R g and R h are independently selected from C 1~6 alkyl; R 25 is C 1~6 alkyl, C 1~6 alkanoyl, C 1~6 alkylsulfonyl, C 1~6 alkoxycarbonyl, carbamoyl, N-(C 1~6 alkyl)carbamoyl, N,N-(C 1~6 alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl, or a pharmaceutically acceptable salt thereof. Or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the ASBT inhibitor is a compound of formula (II):

[0027]

Chemical formula

[0028] (wherein, R v and R w are each independently selected from hydrogen or C 1~6 alkyl; R 1 and R 2 are each independently selected from C 1~6 alkyl; R x and R y are each independently selected from hydrogen or C 1~6 alkyl, or one of R x and R y is hydrogen or C 1~6 alkyl and the other is hydroxy or C 1~6 alkoxy; R z is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6 alkanoyl, C 1~6 alkanoyloxy, N-(C 1~6 alkyl)amino, N,N-(C 1~6 alkyl) 2 amino, C 1~6 alkanoylamino, N-(C 1~6 alkyl)carbamoyl, N,N-(C 1~6 alkyl) 2 carbamoyl, C where a is 0 - 2 1~6 alkylS(O) a , C 1~6 alkoxycarbonyl, C 1~6 alkoxycarbonylamino, ureido, N'-(C 1~6 alkyl)ureido, N-(C 1~6 alkyl)ureido, N',N'-(C 1~6 alkyl) 2 ureido, N'-(C 1~6 alkyl)-N-(C 1~6 alkyl)ureido, N',N'-(C 1~6 alkyl) 2 -N-(C1~6 (alkyl)ureido, N-(C 1~6 (alkyl)sulfamoyl and N,N-(C 1~6 (alkyl) 2 selected from the group consisting of; v is from 0 to 5; R 4 and R 5 one of is a group of formula (IIA):

[0029]

Chemical formula

[0030] wherein R 3 and R 6 , and R 4 and R 5 the other is independently hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1~4 alkyl, C 2~4 alkenyl, C 2~4 alkynyl, C 1~4 alkoxy, C 1~4 alkanoyl, C 1~4 alkanoyloxy, N-(C 1~4 (alkyl)amino, N,N-(C 1~4 (alkyl) 2 amino, C 1~4 alkanoylamino, N-(C 1~4 (alkyl)carbamoyl, N,N-(C 1~4 (alkyl) 2 carbamoyl, C where a is from 0 to 2 1~4 alkylS(O) a , C 1~4 alkoxycarbonyl, N-(C 1~4 (alkyl)sulfamoyl and N,N-(C 1~4 (alkyl) 2 selected from the group consisting of; wherein, R 3 and R 6 , and R 4 and R 5On the other hand, one or more R's are optionally substituted on carbon; 16 and may be optionally substituted by 16 ; D is -O-, -Ν(R a )-, -S(O) b - or -CH(R a )-; where R a is hydrogen or C 1~6 alkyl, and b is 0 to 2; Ring A is aryl or heteroaryl; where ring A is optionally substituted by one or more substituents selected from R 17 ; R 7 is hydrogen, C 1~4 alkyl, carbocyclic or heterocyclic; where R 7 is optionally substituted by one or more substituents selected from R 18 ; R 8 is hydrogen or C 1~4 alkyl; R 9 is hydrogen or C 1~4 alkyl; R 10 is hydrogen, C 1~4 alkyl, carbocyclic or heterocyclic; where R 10 is optionally substituted by one or more substituents selected from R 19 ; R 11 is carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(OR c )(OR d ), -P(O)(OH)(OR c ), -P(O)(OH)(R d ) and -P(O)(OR c )(R d ) selected from the group consisting of; where R c and R d are independently selected from C 1~6 alkyl; or R 11 is a group of formula (IIB):

[0031] [Chemical formula]

[0032] (wherein, X is -N(R q )-, -N(R q )C(O)-, -O-, or -S(O) a -; here, a is 0 to 2, and R q is hydrogen or C 1~4 alkyl; R 12 is hydrogen or C 1~4 alkyl; R 13 and R 14 are independently selected from the group consisting of hydrogen, C 1~4 alkyl, carbocyclic, heterocyclic, and R 23 ; here, the C 1~4 alkyl, carbocyclic, or heterocyclic may optionally be substituted by one or more substituents selected from R 20 ; R 15 is carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(OR e )(OR f ), -P(O)(OH)(OR e ), -P(O)(OH)(R e ), and -P(O)(OR e )(R f ), where R e and R f are independently selected from C 1~6 alkyl; or R 15 is a group of formula (IIC):

[0033] [Chemical formula]

[0034] (wherein, R 24 is hydrogen or C1~4 is alkyl; R 25 is hydrogen, C 1~4 alkyl, carbocyclic, heterocyclic and R 27 is selected from the group consisting of; wherein said C 1~4 alkyl, carbocyclic or heterocyclic may optionally be substituted by one or more substituents selected from R 28 ; R 26 is carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(OR g )(OR h ), -P(O)(OH)(OR g ), -P(O)(OH)(R g ) and -P(O)(OR g )(R h ) and is selected from the group consisting of, wherein R g and R h are independently selected from C 1~6 alkyl) ; p is from 1 to 3; wherein the values of R 13 may be the same or different; q is from 0 to 1; r is from 0 to 3; wherein the values of R 14 may be the same or different) ; m is from 0 to 2; wherein the values of R 10 may be the same or different; n is from 1 to 3; wherein the values of R 7 may be the same or different; z is from 0 to 3; wherein the values of R 25 may be the same or different; R 16 , R 17 and R 18 are each independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1~4 alkyl, C 2~4Alkenyl, C 2~4 Alkynyl, C 1~4 Alkoxy, C 1~4 Alkanoyl, C 1~4 Alkanoyloxy, N-(C 1~4 Alkyl)amino, N,N-(C 1~4 Alkyl) 2 Amino, C 1~4 Alkanoylamino, N-(C 1~4 Alkyl)carbamoyl, N,N-(C 1~4 Alkyl) 2 Carbamoyl, C where a is 0 - 2 1~4 AlkylS(O) a 、C 1~4 Alkoxycarbonyl, N-(C 1~4 Alkyl)sulfamoyl and N,N-(C 1~4 Alkyl) 2 Sulfamoyl, selected from the group consisting of; Here, R 16 、R 17 and R 18 may optionally be substituted by one or more R 21 on carbon; R 19 、R 20 、R 23 、R 27 and R 28 are each independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~4 Alkoxy, C 1~4 Alkanoyl, C 1~4 Alkanoyloxy, N-(C 1~4 Alkyl)amino, N,N-(C 1~4 Alkyl) 2 Amino, C 1~4 Alkanoylamino, N-(C 1~4 Alkyl)carbamoyl, N,N-(C 1~4 Alkyl) 2 Carbamoyl, C where a is 0 - 2 1~4 AlkylS(O) a 、C1~4 Alkoxycarbonyl, N-(C 1~4 alkyl)sulfamoyl, N,N-(C 1~4 alkyl) 2 sulfamoyl, carbocyclic, heterocyclic, sulfo, sulfino, amidino, phosphono, -P(O)(OR a )(OR b ), -P(O)(OH)(OR a ), -P(O)(OH)(R a ), or -P(O)(OR a )(R b ), selected from the group consisting of, wherein R a and R b are independently selected from C 1~6 alkyl; wherein R 19 , R 20 , R 23 , R 27 and R 28 may optionally be substituted on carbon by one or more R 22 ; R 21 and R 22 are independently selected from the group consisting of halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamide, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N,N-dimethylsulfamoyl) or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the ASBT inhibitor is a compound of formula (III):

[0036]

Chemical formula

[0037] (wherein, q is an integer from 1 to 4; n is an integer from 0 to 2; R 1 and R 2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl are optionally 9 OR 9 R 10 N + R 9 R 10 R w A - SR 9 S + R 9 R 10 A - .P + R 9 R 10 R 11 A - S(O)R 9 SO 2 R 9 SO 3 R 9 CO 2 R 9 CN, halogen, oxo, and CONR 9 R 10 optionally substituted with one or more substituents selected from the group consisting of, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl are optionally, in some cases, one or more carbons replaced with O, NR 9 N + R 9 R 10 A - S, SO, SO 2, S + R 9 A - , P + R 9 R 10 A - or replaced by phenylene, R 9 、R 10 、and R w are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carbalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammonium alkyl; or R 1 and R 2 together with the carbon to which they are attached form a C 3~10 cycloalkyl; R 3 and R 4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR 9 , NR 9 R 10 , SR 9 , S(O)R 9 , SO 2 R 9 , and SO 3 R 9 wherein R 9 and R 10 are as defined above; or R 3 and R 4 together form =O, =NOR 11 , =S, =NNR 11 R 12 , =NR 9 , or =CR 11 R 12 to form, wherein R 11 and R 12is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 , NR 9 R 10 , SR 9 , S(O)R 9 , SO 2 R 9 , SO 3 R 9 , CO 2 R 9 , CN, halogen, oxo, and CONR 9 R 10 wherein R 9 and R 10 are as defined above, provided that R 3 and R 4 are not both OH, NH 2 , and SH, or R 11 and R 12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R 5 is aryl substituted with one or more OR 13a , wherein R 13a is selected from the group consisting of alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl, R 13a is hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR 9 , NR 9 R 10 , N + R 9 R 11 R12 A - 、 SR 9 、 S(O)R 9 、 SO 2 R 9 、 SO 3 R 9 、 oxo, CO 2 R 9 、 CN, halogen, CONR 9 R 10 、 SO 2 OM, SO 2 NR 9 R 10 、 PO(OR 16 )OR 17 、 P + R 9 R 10 R 11 A - 、 S + R 9 R 10 A - 、 and optionally substituted with one or more groups selected from the group consisting of C(O)OM, wherein A - is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, wherein R 16 and R 17 are independently selected from the substituents that make up R 9 and M; R 6 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR 30 、 SR 9 、 S(O)R 9 、 SO 2 R 9 、 and SO 3 R 9 selected from the group consisting of, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR 13 、 NR 13 R14 , SR 13 , S(O)R 13 , SO 2 R 13 , SO 3 R 13 , NR 13 OR 14 , NR 13 NR 14 R 15 , NO 2 , CO 2 R 13 , CN, OM, SO 2 OM, SO 2 , NR 13 R 14 , C(O)NR 13 R 14 , C(O)OM, COR 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 14 R 15 , NR 13 CO 2 R 14 , OC(O)R 13 , OC(O)NR 13 R 14 , NR 13 SOR 14 , NR 13 SO 2 R 14 , NR 13 SONR 14 R 15 , NR 13 SO 2 NR 14 R 15 , P(O)R 13 R 14 , P + R 13 R 14 R 15 A - , P(OR 13 )OR 14 , S + R 13 R 14 A - , and N + R 9 R 11 R 12 A -optionally substituted with one or more substituents independently selected from the group consisting of: A - is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle are each independently selected from the group consisting of OR 7 , NR 7 R 8 , SR 7 , S(O)R 7 , SO 2 R 7 , SO 3 R 7 , CO 2 R 7 , CN, oxo, CONR 7 R 8 , N + R 7 R 8 R 9 A - , alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 R 8 P + R 7 R 8 R 9 A - , and P(O)(OR 7 )OR 8 optionally further substituted with one or more substituents selected from the group consisting of: wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle may optionally contain one or more carbon atoms replaced by O, NR 7 , N + R 7 R 8 A - , S, SO, SO 2 , S + R 7 A - , PR 7 , P(O)R 7 , P + R 7 R8 A - 、 or may be replaced by phenylene, R 13 、R 14 、 and R 15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl may optionally have one or more carbons replaced by O, NR 9 、N + R 9 R 10 A - 、S, SO, SO 2 、S + R 9 A - 、PR 9 、P + R 9 R 10 A - 、P(O)R 9 、 phenylene, carbohydrate, amino acid, peptide, or polypeptide, R 13 、R 14 、 and R 15 are hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR 9 、NR 9 R 10 、N + R 9 R 11 R 12 A - 、SR 9 、S(O)R9 , SO 2 R 9 , SO 3 R 9 , oxo, CO 2 R 9 , CN, halogen, CONR 9 R 10 , SO 2 OM, SO 2 NR 9 R 10 , PO(OR 16 )OR 17 , P + R 9 R 10 R 11 A - , S + R 9 R 10 A - , and optionally substituted with one or more groups selected from the group consisting of C(O)OM, wherein R 16 and R 17 are independently selected from the substituents that make up R 9 and M; or R 13 and R 14 together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle optionally substituted with one or more groups selected from the group consisting of oxo, carboxy and quaternary salts; or R 14 and R 15 together with the nitrogen atom to which they are attached form a cyclic ring; R 30 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylammonium alkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboxyalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammonium alkyl; R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; One or more Rs x are independently H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR 13 , NR 13 R 14 , SR 13 , S(O)R 13 , S(O) 2 R 13 , SO 3 R 13 , S + R 13 R 14 A - , NR 13 OR 14 , NR 13 , NR 14 R 15 , NO 2 , CO 2 R 13 , CN, OM, SO 2 OM, SO 2 , NR 13 R 14 , NR 14 C(O)R 13 , C(O)NR 13 R 14 , NR 14 C(O)R 13 , C(O)OM, COR 13 , OR 18 , S(O) n , NR 18 , NR 13 R 18 , NR 18 , OR 14 , N + R 9 R 11 R 12 A - , P + R 9 R 11 R 12 A - and are selected from the group consisting of amino acids, peptides, polypeptides, and carbohydrates, Here, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocyclic, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocyclic, and quaternary heteroaryl are OR 9 , NR 9 R 10 , N + R 9 R 11 R 12 A - , SR 9 , S(O)R 9 , SO 2 R 9 , SO 3 R 9 , oxo, CO 2 R 9 , CN, halogen, CONR 9 R 10 , SO 2 OM, SO 2 , NR 9 R 10 , PO(OR 16 )OR 17 , P + R 9 R 11 R 12 A - , S + R 9 R 10 A - , or may be further substituted with C(O)OM, where R 18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocyclic, heteroaryl, alkyl, where acyl, arylalkoxycarbonyl, arylalkyl, heterocyclic, heteroaryl, alkyl, quaternary heterocyclic, and quaternary heteroaryl are OR 9 , NR 9 R 10 , N + R 9 R 11 R 12 A - , SR 9 , S(O)R 9 , SO 2 R 9 , SO 3 R9 、 oxo, CO 2 R 9 、 CN, halogen, CONR 9 R 10 、 SO 3 R 9 、 SO 2 OM, SO 2 NR 9 R 10 、 PO(OR 16 )OR 17 、 and optionally substituted with one or more substituents selected from the group consisting of C(O)OM; wherein, R x in which one or more carbons are optionally replaced by O, NR 13 、 N + R 13 R 14 A - 、 S, SO, SO 2 、 S + R 13 A - 、 PR 13 、 P(O)R 13 、 P + R 13 R 14 A - 、 phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl; wherein, in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR 9 、 N + R 9 R 10 A - 、 S, SO, SO 2 、 S + R 9 A - 、 PR 9 、 P + R 9 R 10 A - 、 or P(O)R 9 ; Here, the quaternary heterocycle and the quaternary heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR, 13 , N.R. 13 R 14 , S.R. 13 , S(O)R 13 , S.O. 2 R 13 , S.O. 3 R 13 , N.R. 13 OR 14 , N.R. 13 NR 14 R 15 , NO 2 , CO 2 R 13 , C.N., O.M., S.O. 2 OM, SO 2 NR 13 R 14 , C(O)NR 13 R 14 , C(O)OM, COR 13 , P(O)R 13 R 14 , P + R 13 R 14 R 15 A - , P(OR 13 ) OR 14 , S + R 13 R 14 A - , and N + R 9 R 11 R 12 A - and optionally substituted with one or more groups selected from the group consisting of or a pharma- ceutical acceptable salt thereof.

[0038] In some embodiments, the ASBT inhibitor is a compound of formula (IV):

[0039] [ka]

[0040] (wherein, X is O, NH, CH 2 or a bond; R 1 is C 1~6 alkyl; R 2 R 2' R 3 R 3' R 4 R 4' R 5 and R 5' are each independently H, Cl, Br, I, OH, -(CH 2 )-OH, CF 3 NO 2 N 3 CN, S(O) p -R 6 O-S(O) p -R 6 C 1~6 alkylene-S(O) p -R 6 C 1~6 alkylene-O-S(O) p -R 6 COOH, COOC 1~6 alkyl, CONH 2 CONHC 1~6 alkyl, CON(C 1~6 alkyl) 2 C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl and O-C 1~6 alkyl selected from the group consisting of, wherein one or more of the alkyl hydrogens are fluorine; and phenyl, -(CH 2 )-phenyl, -(CH 2 ) n -phenyl, O-phenyl, O-(CH 2 ) m -phenyl, -(CH 2 )-O-(CH 2 ) m -phenyl may be replaced by, wherein the phenyl ring is F, Cl, Br, I, OH, CF 3 NO 2 CN, OCF3 、 O-C 1~6 alkyl, C 1~6 alkyl, NH 2 、 NHC 1~6 alkyl, N(C 1~6 alkyl) 2 、 SO 2 -CH 3 、 COOH, COOC 1~6 alkyl, or CONH 2 and may be substituted 1 to 3 times; Here, always, R 2 、 R 2' 、 R 3 、 R 3' 、 R 4 、 R 4' 、 R 5 、 R 5' of at least one is -O-(CH 2 ) m -phenyl or -(CH 2 )-O-(CH 2 ) m -phenyl, where the phenyl ring is F, Cl, Br, I, OH, CF 3 、 NO 2 、 CN, OCF 3 、 O-C 1~6 alkyl, C 1~6 alkyl, NH 2 、 NHC 1~6 alkyl, N(C 1~6 alkyl) 2 、 SO 2 -CH 3 、 COOH, COOC 1~6 alkyl, CONH 2 and may be substituted 1 to 3 times; R 6 is selected from the group consisting of H, OH, C 1~6 alkyl, NH 2 、 NHC 1~6 alkyl and N(C 1~6 alkyl) 2 ; n is an integer of 2, 3, 4, 5 or 6; m is an integer of 1, 2, 3, 4, 5 or 6; p is an integer of 0, 1 or 2) or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, the ASBT inhibitor is a compound of formula (V):

[0042]

Chemical formula

[0043] (wherein, R 1 is selected from the group consisting of H, Cl, Br, N(CH 3 ) 2 and methoxy; R 2 is H or OH; each R 3 is independently C 1~6 alkyl; X is CH 2 , C(O) or CH=CH; Q is C 0~6 alkyl; R 4 is selected from the group consisting of OH, SO 3 H, CO 2 H, PO 3 H 2 , CONR 5 R 5 , NR 5 R 5 and NHC(O)CH 2 NR 5 R 5 ; each R 5 is independently H, OH, C 1~6 alkyl, C 0~6 alkyl CO 2 H, C 0~6 alkyl SO 3 H, C 0~6 alkyl PO 3 H 2 , C(O)C 0~6 alkyl CO 2 , C(O)C 0~6 alkyl SO 3 , C(O)C 0~6 alkyl PO 3 H2 and CH(R 6 )C 0~6 alkyl CO 2 selected from the group consisting of H; R 6 is C 0~6 alkyl CO 2 H, C 0~6 alkyl OH, C 0~6 alkyl SO 3 H and C 0~6 alkyl PO 3 H 2 selected from the group consisting of) or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the ASBT inhibitor is a compound of formula (VI):

[0045]

Chemical formula

[0046] (wherein, M is selected from -CH 2 - and -NR 7 -; R 1 and R 2 are each independently C 1~4 alkyl; R 3 is hydrogen, halogen, hydroxy, C 1~4 alkyl, C 1~4 haloalkyl, C 1~4 alkoxy, cyano, nitro, amino, N-(C 1~4 alkyl)amino, N,N-di(C 1~4 alkyl)amino, N-(aryl-C 1~4 alkyl)amino, C 1~6 alkylcarbonylamino, C 3~6 cycloalkylcarbonylamino, N-(C 1~4 alkyl)aminocarbonyl, N,N-di(C 1~4 alkyl)aminocarbonyl, C 1~4 alkyloxycarbonylamino, C 3~6Cycloalkyloxycarbonylamino, C 1~4 alkylsulfonamide and C 3~6 selected from the group consisting of cycloalkylsulfonamide; n is an integer of 1, 2 or 3; R 4 is hydrogen, halogen, cyano, C 1~4 alkyl, C 3~6 cycloalkyl, C 1~4 alkoxy, C 3~6 cycloalkyloxy, C 1~4 alkylthio, C 3~6 cycloalkylthio, amino, N-(C 1~4 alkyl)amino and N,N-di(C 1~4 alkyl)amino selected from the group consisting of; R 5 and R 6 one of which is carboxy, R 5 and R 6 the other of which is selected from the group consisting of hydrogen, fluoro, C 1~4 alkyl and C 1~4 haloalkyl; R 7 is selected from the group consisting of hydrogen and C 1~4 alkyl; R 8 is selected from the group consisting of hydrogen and C 1~4 alkyl) or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the ASBT inhibitor is a compound of formula (VII):

[0048]

Chemical formula

[0049] (wherein, M is -CH 2 - or -NR 6 -; R 1 and R 2 are each independently C 1~4is alkyl; R 3 is independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1~4 alkyl, C 1~4 haloalkyl, C 1~4 alkoxy, C 1~4 haloalkoxy, cyano, nitro, amino, N-(C 1~4 alkyl)amino, N,N-di(C 1~4 alkyl)amino and N-(aryl-C 1~4 alkyl)amino; n is an integer of 1, 2 or 3; R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C 1~4 alkyl, C 3~6 cycloalkyl, C 1~4 alkoxy, C 3~6 cycloalkyloxy, C 1~4 alkylthio, C 3~6 cycloalkylthio, amino, N-(C 1~4 alkyl)amino and N,N-di(C 1~4 alkyl)amino; R 5A , R 5B , R 5C and R 5D are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1~4 alkyl and C 1~4 alkoxy; R 6 is selected from the group consisting of hydrogen and C 1~4 alkyl) or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the ASBT inhibitor is a compound of formula (VIII):

[0051]

Chemical formula

[0052] (wherein, M is -CH2 -or -NH-; R 1 and R 2 are each independently, C 1~4 alkyl; R 3 is independently hydrogen, halogen, hydroxy, C 1~4 alkyl, C 1~4 haloalkyl, C 1~4 alkoxy, C 1~4 haloalkoxy, cyano, nitro, amino, N-(C 1~4 alkyl)amino, N,N-di(C 1~4 alkyl)amino, and N-(aryl-C 1~4 alkyl)amino selected from the group consisting of; n is an integer of 1, 2 or 3; R 4 is hydrogen, halogen, hydroxy, cyano, C 1~4 alkyl, C 3~6 cycloalkyl, C 1~4 alkoxy, C 3~6 cycloalkyloxy, C 1~4 alkylthio, C 3~6 cycloalkylthio, amino, N-(C 1~4 alkyl)amino and N,N-di(C 1~4 alkyl)amino selected from the group consisting of) or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the ASBT inhibitor is a compound of formula (IX):

[0054]

Chemical formula

[0055] (wherein, M is selected from -CH 2 - and -NR 6 -; R 1 is C 1~4 alkyl; R 2are independently hydrogen, halogen, hydroxy, C 1~4 alkyl, C 1~4 haloalkyl, C 1~4 alkoxy, cyano, nitro, amino, N-(C 1~4 alkyl)amino, N,N-di(C 1~4 alkyl)amino, N-(aryl-C 1~4 alkyl)amino, C 1~6 alkylcarbonylamino, C 3~6 cycloalkylcarbonylamino, N-(C 1~4 alkyl)aminocarbonyl, N,N-di(C 1~4 alkyl)aminocarbonyl, C 1~4 alkyloxycarbonylamino, C 3~6 cycloalkyloxycarbonylamino, C 1~4 alkylsulfonamide and C 3~6 cycloalkylsulfonamide selected from the group consisting of; n is an integer of 1, 2 or 3; R 3 is hydrogen, halogen, cyano, C 1~4 alkyl, C 3~6 cycloalkyl, C 1~4 alkoxy, C 3~6 cycloalkyloxy, C 1~4 alkylthio, C 3~6 cycloalkylthio, amino, N-(C 1~4 alkyl)amino and N,N-di(C 1~4 alkyl)amino selected from the group consisting of; R 4 and R 5 one of is carboxyl, R 4 and R 5 the other of is selected from the group consisting of hydrogen, fluoro, C 1~4 alkyl and C 1~4 haloalkyl; R 6 is selected from the group consisting of hydrogen and C 1~4 alkyl; R 7 is selected from the group consisting of hydrogen and C 1~4 alkyl) or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the ASBT inhibitor is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{ (R)-1'-phenyl-1'-[N'-(carboxymethyl)-carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{ (R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1-{[4-({4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-1λ 6 -benzothiepin-5-yl]phenoxy}methyl)phenyl]methyl}-1,4-diazabicyclo[2.2.2]octan-1-ium chloride; N-(3-O-benzyl-6-O-sulfo-β-D-glucopyranosyl)-N'-{3-[(3S,4R,5R)-3-butyl-7-(dimethylamino)-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-1λ 6 -benzothiepin-5-yl]phenyl}urea; 3-({[(3R,5R)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1λ 6 ,4-benzothiazepin-8-yl]methyl}amino)pentanedioic acid; (Z)-3-((3,3-dibutyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)oxy)-2-fluoroacrylic acid; (Z)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-fluoroacrylic acid; 3-((7-bromo-3-butyl-3-ethyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)propanoic acid; 3-((3,3-dibutyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-hydroxypropanoic acid; 3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)propanoic acid; 3-((3,3-dibutyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)propanoic acid; 3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)propanoic acid; 2-((3-butyl-7-(dimethylamino)-3-ethyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acetic acid; 2-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo-1,2,5-thiadiazepin-8-yl)oxy)acetic acid; and (E)-3-((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acrylic acid A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the ASBT inhibitor is

[0058]

Chemical formula

[0059] (erobixibat)

[0060]

Chemical formula

[0061] (odevixibat)

[0062]

Chemical formula

[0063] (maralixibat)

[0064]

Chemical formula

[0065] (borexibat)

[0066]

Chemical formula

[0067] (linacixibat) a compound selected from or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the ASBT inhibitor is elobixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the ASBT inhibitor is odesivibat or a pharmaceutically acceptable salt thereof. In some embodiments, the ASBT inhibitor is maralixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the ASBT inhibitor is volixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the ASBT inhibitor is linacixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the ASBT inhibitor comprises elobixibat, odesivibat, maralixibat, volixibat, and linacixibat, or a combination of two or more of their pharmaceutically acceptable salts.

[0069] As used herein, the term "halo" refers to fluoro, chloro, bromo, and iodo.

[0070] As used herein, "C 1~6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and "C 1~4 alkyl" refers to a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples of C 1~4 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0071] As used herein, "C 1~4 haloalkyl" refers to a straight-chain or branched C 1~4 alkyl group as defined herein, wherein one or more hydrogen atoms are replaced by halogen. Examples of C 1~4 haloalkyl include chloromethyl, fluoroethyl, and trifluoromethyl.

[0072] As used herein, "C 1~4 alkoxy" and "C 1~4The term "alkylthio" refers to a linear or branched C alkyl group bonded through an oxygen or sulfur atom, respectively, to the remainder of the molecule. 1~4

[0073] As used herein, the term "C 3~6 cycloalkyl" refers to a monocyclic saturated hydrocarbon ring having 3 to 6 carbon atoms. Examples of C 3~6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0074] The term "amino" refers to an -NH 2 group. As used herein, the terms "N-(C 1~4 alkyl)amino" and "N,N-di(C 1~4 alkyl)amino" refer to an amino group in which one or both hydrogen atoms are each replaced by a linear or branched C 1~4 alkyl group. Examples of N-(C 1~4 alkyl)amino include methylamino, ethylamino, and tert-butylamino, and examples of N,N-di-(C 1~4 alkyl)amino include dimethylamino and diethylamino.

[0075] The term "aryl" refers to an aromatic monocyclic ring composed of 6 carbon atoms or an aromatic bicyclic ring system composed of 10 carbon atoms. Examples of aryl include phenyl, naphthyl, and azulenyl.

[0076] As used herein, the term "N-(aryl-C 1~4 alkyl)amino" refers to an amino group in which the hydrogen atom is replaced by an aryl-C 1~4 alkyl group. Examples of N-(aryl-C 1~4 alkyl)amino include benzylamino and phenylethylamino. The term "C 1~6 alkylcarbonylamino" refers to an amino group in which the hydrogen atom is C 1~6 ​Refers to an amino group substituted with an alkylcarbonyl group. C 1~6 Examples of alkanoylamino include acetylamino and tert-butylcarbonylamino. "C 1~4 The term "C 1~4 alkylcarbonyloxycarbonylamino" refers to an amino group in which a hydrogen atom is replaced by a C 1~4 alkylcarbonyloxycarbonyl group. Examples of C 1~4 alkylcarbonyloxycarbonylamino are tert-butoxycarbonylamino. "C 3~6 alkylsulfonamide" and "C 1~4 cycloalkylsulfonamide" refer to amino groups in which a hydrogen atom is replaced by a C 3~6 alkylsulfonyl or a C

[0077] Some ASBT inhibitors or pharmaceutically acceptable salts thereof may have chiral centers and / or geometric isomerism centers (E- and Z-isomers). It should be understood that the present invention encompasses all such optical isomers, diastereoisomers and geometric isomers having ASBT inhibitory activity. The present invention also encompasses any and all tautomers having ASBT inhibitory activity. Certain ASBT inhibitors or pharmaceutically acceptable salts thereof may exist not only in the non-solvated form but also in a solvated form such as, for example, the hydrated form. It should be understood that the present invention encompasses all such solvated forms having ASBT inhibitory activity.

[0078] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable for human pharmaceutical use, generally safe and non-toxic, and not biologically or otherwise undesirable.

[0079] Suitable salts of the ASBT inhibitor that are pharmaceutically acceptable are, for example, base addition salts of the compound that are sufficiently acidic, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), ammonium salts, or salts with organic bases that yield physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0080] Liver and kidney diseases Liver disease, as defined herein, is any disease in the liver and related organs such as the pancreas, portal vein, liver parenchyma, intrahepatic biliary system, extrahepatic biliary system, and gallbladder. In some embodiments, the liver or kidney disease or disorder is a bile acid-dependent disease or disorder, i.e., a disease or disorder in which bile acids are involved in the onset or progression of the disease or disorder.

[0081] In some embodiments, the liver or kidney disease or disorder includes an impairment or defect in bile flow.

[0082] In some embodiments, the liver or kidney disease or disorder includes cholestasis. In some embodiments, the accumulation of bile acids occurs in the extrahepatic biliary system (extrahepatic or obstructive cholestasis). In some embodiments, the accumulation of bile acids occurs in the intrahepatic biliary system (intrahepatic cholestasis).

[0083] In some embodiments, the liver disease or disorder is PFIC type 2. PFIC-2 is caused by a disorder of bile salt secretion due to a mutation in the ABCB11 gene, which encodes a protein known as BSEP (bile salt export pump) that transports bile acids out of the liver. Subjects with PFIC-2 often develop liver failure within the first few years of life and have a high risk of developing a certain type of liver cancer known as hepatocellular carcinoma.

[0084] Van Wessel et al. (J. Hepatol. 2020, Vol. 73, pp. 84-93) classified BSEP deficiency into three groups based on the type of ABCB11 gene mutations. BSEP1 patients have at least one p.D482G (c.1445A>G) or p.E297G (c.890A>G) mutation. With either of these mutations, some BSEP protein is still produced, but not enough. BSEP2 patients have at least one missense mutation that is neither p.D482G nor p.E297G. Many different mutations have been found in patients in this group. Finally, BSEP3 patients have mutations that are known or predicted to result in non-functional BSEP protein or absence of BSEP expression. The type of ABCB11 gene mutation is related to the severity of the disease, with BSEP1 deficiency causing a less severe disease and BSEP3 deficiency causing the most severe disease. In some embodiments of the present invention, the liver disease or disorder includes BSEP3 deficiency.

[0085] In some embodiments, the liver disease or disorder includes biliary obstruction, where the biliary obstruction is an obstruction of one or more bile ducts. The biliary obstruction can be caused by inflammation of the bile ducts (leading to cholangitis); by gallstones (leading to choledocholithiasis); or by tumors and neoplasms of the liver (e.g., liver cancer), the biliary tract (such as cholangiocarcinoma and gallbladder cancer), or the pancreas (pancreatic cancer). Alternatively, the biliary obstruction can be caused by a congenital or acquired condition such as biliary atresia. Biliary atresia is a rare pediatric liver disease that involves partial or complete obstruction of the large bile ducts or even the complete absence of the large bile ducts. This obstruction or absence causes cholestasis, which leads to the accumulation of bile acids that damage the liver. In some embodiments, the accumulation of bile acids occurs in the extrahepatic biliary system. In some embodiments, the accumulation of bile acids occurs in the intrahepatic biliary system. Currently, there is no approved drug therapy for this disorder. The current standard treatment is the Kasai procedure, which is a surgical operation to remove the obstructed bile ducts and connect a part of the small intestine directly to the liver. Nevertheless, problems related to the obstruction of bile flow and the accumulation of bile acids in the liver typically remain, and most patients ultimately require a liver transplant. Therefore, the treatment of biliary atresia includes the treatment of biliary atresia after the Kasai procedure and the treatment of biliary atresia after liver transplantation.

[0086] In some embodiments, the liver disease or disorder is caused by inflammation of the bile ducts, such as in acute cholangitis and obstructive cholangitis. The inflammation is often the result of an obstruction of the biliary tract, such as by gallstones, but can also be caused by, for example, a tumor or a blood infection, or can occur after an endoscopic examination of the liver or gallbladder.

[0087] In some embodiments, the liver disease or disorder is a malignant biliary obstruction, such as a malignant biliary obstruction caused by cholangiocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma), gallbladder cancer, or colon cancer.

[0088] ASBT inhibitors may play an important role in mediating the toxic effects of bile acids in the kidney. It has been observed that ASBT is strongly downregulated after bile duct ligation (BDL) in mice, and inhibition of renal ASBT significantly improves cholestatic nephropathy in mice. Therefore, inhibition of ASBT may have a protective effect on the kidney, especially in patients with advanced liver disease.

[0089] In some embodiments, the kidney disease or disorder is a bile acid-dependent disease or disorder, i.e., a disease or disorder in which bile acids are involved in the onset or progression of the disease or disorder.

[0090] In some embodiments, the kidney disease or disorder is selected from the group consisting of cholestatic nephropathy, chronic nephritis, hyperbilirubinemia, renal dysfunction in obstructive jaundice, age-related impairment of mitochondrial function in the kidney, kidney inflammation, acute kidney injury (AKI), renal ischemia / reperfusion injury (IRI), chronic kidney disease (CKD), polycystic kidney disease (PKD), arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome, familial lecithin cholesterol acyltransferase (LCAT) deficiency, chronic renal failure, end-stage renal disease (ESRD), proximal tubular injury in the kidney, type 1 hepatorenal syndrome, type 2 hepatorenal syndrome, and acute exacerbation of chronic liver disease.

[0091] In some embodiments, the kidney disease or disorder is cholestatic nephropathy, which is a state of renal injury / insufficiency in patients with obstructive jaundice. Cholestatic nephropathy, also known as cholestatic cylindruria, bile acid nephropathy, icteric nephrosis / nephritis or jaundice-related nephropathy, is an underestimated but important cause of renal dysfunction in cholestasis with jaundice or advanced liver disease. This is a common complication in patients with liver diseases such as cirrhosis, alcoholic fatty hepatitis, drug-induced cholestatic liver injury and fulminant hepatitis, and is associated with high morbidity and mortality. Cholestatic nephropathy is characterized by hemodynamic changes in the liver, kidney, systemic circulation, intratubular cylindruria, and tubular epithelial cell injury, but the underlying pathophysiological mechanism is still not fully understood.

[0092] Toxic bile acids have been suggested to play a role in the development of kidney injury in cholestasis (Fickert et al., Hepatology 2013, Vol. 58, pp. 2056 - 2069; Krones et al., Dig. Dis. 2015, Vol. 33, pp. 367 - 375; Tinti et al., Life 2021, Vol. 11, 1200). Norursodeoxycholic acid, a less toxic bile acid, has been shown to improve kidney injury and has been proposed as a treatment for cholestatic nephropathy (Krones et al., J Hepatol. 2017, Vol. 67, pp. 110 - 119). Currently, there is no specific treatment available for this condition.

[0093] In some embodiments, subcutaneous administration of an ASBT inhibitor is combined with oral administration of an ASBT inhibitor, such as a non - systemically absorbed ASBT inhibitor, or with oral administration of an LBAT inhibitor. Such combination therapies may have additive or synergistic effects and may result in the excretion of even larger amounts of bile acids. Examples of non - systemically absorbed ASBT inhibitors include, but are not limited to, elobixibat, odesivixibat, maralixibat, volixibat, and linelixibat. The systemic absorption after oral administration of these ASBT inhibitors is less than 10%. Further examples of suitable ASBT inhibitors are disclosed, for example, in WO 2019 / 234077, WO 2020 / 161216, WO 2020 / 161217, WO 2021 / 110884, WO 2021 / 110885, WO 2021 / 110886, WO 2021 / 110887, and WO 2022 / 029101. Examples of suitable LBAT inhibitors are disclosed, for example, in WO 2021 / 110883, WO 2022 / 117778, and WO 2022 / 253997.

[0094] In some embodiments, the patient does not respond to treatment with an orally administered non - systemically absorbed ASBT inhibitor. Since subcutaneous administration of an ASBT inhibitor leads to the regulation of ASBT in the kidney, it is considered that subcutaneous administration of an ASBT inhibitor may provide a more potent ASBT - regulating effect than oral administration of the compound.

[0095] In some embodiments, for example, if a patient experiences severe side effects such as severe diarrhea, the patient has no tolerance to treatment with an orally administered non-systemically absorbed ASBT inhibitor. Subcutaneous administration of an ASBT inhibitor also results in the regulation of ASBT in the kidney, so that bile acids are excreted not only in feces but also in urine. This is expected to lead to a reduction in the incidence of diarrhea.

[0096] Also provided herein is a method for treating a liver or kidney disease or disorder in a subject in need thereof, the method comprising the step of subcutaneously administering to the subject a therapeutically effective amount of an ASBT inhibitor. Also provided herein is the use of an ASBT inhibitor in the manufacture of a medicament for treating a liver or kidney disease or disorder in which the ASBT inhibitor is subcutaneously administered.

[0097] In some embodiments, after subcutaneous administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject exhibits a reduction in serum bile acid concentration of at least 50% (e.g., 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%) relative to baseline. In some embodiments, the subject exhibits a reduction in serum bile acid concentration of at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline. In some embodiments, after subcutaneous administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject exhibits a reduction in serum bile acid concentration of about 50% to about 95% (e.g., about 50% to about 90%, about 50% to about 85%, about 50% to about 80%, about 50% to about 75%, about 50% to about 70%, about 50% to about 65%, about 50% to about 60%, about 50% to about 55%, about 55% to about 95%, about 55% to about 90%, about 55% to about 85%, about 55% to about 80%, about 55% to about 75%, about 55% to about 70%, about 55% to about 65%, about 55% to about 60%, about 60% to about 95%, about 60% to about 90%, about 60% to about 85%, about 60% to about 80%, about 60% to about 75%, about 60% to about 70%, about 60% to about 65%, about 65% to about 95%, about 65% to about 90%, about 65% to about 85%, about 65% to about 80%, about 65% to about 75%, about 65% to about 70%, about 70% to about 95%, about 70% to about 90%, about 70% to about 85%, about 70% to about 80%, about 70% to about 75%, about 75% to about 95%, about 75% to about 90%, about 75% to about 85%, about 75% to about 80%, about 80% to about 95%, about 80% to about 90%, about 80% to about 85%, about 85% to about 95%, about 85% to about 90%, or about 90% to about 95%) relative to baseline. In some embodiments, the serum bile acid concentration is normalized after subcutaneous administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof.In some embodiments, the serum bile acid concentration is normalized after subcutaneous administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, and the like.

[0098] In some embodiments, after subcutaneous administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject shows an increase in urinary bile acids of at least 50% (e.g., 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%) relative to baseline. In some embodiments, the subject shows an increase in urinary bile acids of at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline. In some embodiments, after subcutaneous administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject shows an increase in urinary bile acids of about 50% to about 95% (e.g., about 50% to about 90%, about 50% to about 85%, about 50% to about 80%, about 50% to about 75%, about 50% to about 70%, about 50% to about 65%, about 50% to about 60%, about 50% to about 55%, about 55% to about 95%, about 55% to about 90%, about 55% to about 85%, about 55% to about 80%, about 55% to about 75%, about 55% to about 70%, about 55% to about 65%, about 55% to about 60%, about 60% to about 95%, about 60% to about 90%, about 60% to about 85%, about 60% to about 80%, about 60% to about 75%, about 60% to about 70%, about 60% to about 65%, about 65% to about 95%, about 65% to about 90%, about 65% to about 85%, about 65% to about 80%, about 65% to about 75%, about 65% to about 70%, about 70% to about 95%, about 70% to about 90%, about 70% to about 85%, about 70% to about 80%, about 70% to about 75%, about 75% to about 95%, about 75% to about 90%, about 75% to about 85%, about 75% to about 80%, about 80% to about 95%, about 80% to about 90%, about 80% to about 85%, about 85% to about 95%, about 85% to about 90%, or about 90% to about 95%) relative to baseline.

[0099] In some embodiments, the presence of a disease listed herein, such as biliary atresia or cholemic nephrosis, is determined by one or more biomarkers indicative of one or more of biliary obstruction, cholestasis, inflammation, hepatic fibrosis, cirrhosis, and / or their scoring system. In some embodiments, the severity of a disease listed herein, such as biliary atresia or cholemic nephrosis, is determined by one or more biomarkers indicative of one or more of biliary obstruction, cholestasis, inflammation, hepatic fibrosis, cirrhosis, and / or their scoring system. In some embodiments, the outcome of treatment of a disease listed herein, such as biliary atresia or cholemic nephrosis, is determined by one or more biomarkers indicative of one or more of biliary obstruction, cholestasis, inflammation, hepatic fibrosis, cirrhosis, and / or their scoring system. Non-limiting examples of biomarkers indicative of one or more of biliary obstruction, cholestasis, inflammation, hepatic fibrosis, cirrhosis, and / or their scoring system include alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), serum bilirubin, prothrombin time (PT), international normalized ratio (INR), total protein, and albumin levels (see, e.g., Lala et al., “Liver Function Tests.” StatPearls, StatPearls Publishing, October 5, 2022 (PMID:29494096), which is incorporated herein by reference in its entirety). In some embodiments, the subject shows improvement in liver parameters (biomarkers) after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the level of alkaline phosphatase (ALP) does not increase. In some embodiments, the level of alkaline phosphatase (ALP) decreases. In some embodiments, the “level” of an enzyme refers to the concentration of the enzyme, e.g., the concentration in the blood. For example, the level of ALP can be expressed as units / L.

[0100] In some embodiments, the total bilirubin level in serum decreases after subcutaneous administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the total bilirubin level is from about 0.5 mg / dL to about 15.0 mg / dL or from about 1 mg / dL to about 10.0 mg / dL (e.g., about 2.0 mg / dL to about 10.0 mg / dL, about 3.0 mg / dL to about 10.0 mg / dL, about 4.0 mg / dL to about 10.0 mg / dL, about 5.0 mg / dL to about 10.0 mg / dL, about 6.0 mg / dL to about 10.0 mg / dL, about 7.0 mg / dL to about 10.0 mg / dL, about 8.0 mg / dL to about 10.0 mg / dL, about 9.0 mg / dL to about 10.0 mg / dL, about 1.0 mg / dL to about 9.0 mg / dL, about 2.0 mg / dL to about 9.0 mg / dL, about 3.0 mg / dL to about 9.0 mg / dL, about 4.0 mg / dL to about 9.0 mg / dL, about 5.0 mg / dL to about 9.0 mg / dL, about 6.0 mg / dL to about 9.0 mg / dL, about 7.0 mg / dL to about 9.0 mg / dL, about 8.0 mg / dL to about 9.0 mg / dL, about 1.0 mg / dL to about 8.0 mg / dL, about 2.0 mg / dL to about 8.0 mg / dL, about 3.0 mg / dL to about 8.0 mg / dL, about 4.0 mg / dL to about 8.0 mg / dL, about 5.0 mg / dL to about 8.0 mg / dL, about 6.0 mg / dL to about 8.0 mg / dL, about 7.0 mg / dL to about 8.0 mg / dL, about 1.0 mg / dL to about 7.0 mg / dL, about 2.0 mg / dL to about 7.0 mg / dL, about 3.0 mg / dL to about 7.0 mg / dL, about 4.0 mg / dL to about 7.0 mg / dL, about 5.0 mg / dL to about 7.0 mg / dL, about 6.0 mg / dL to about 7.0 mg / dL, about 1.0 mg / dL to about 6.0 mg / dL, about 2.0 mg / dL to about 6.0 mg / dL, about 3.0 mg / dL to about 6.0 mg / dL, about 4.0 mg / dL to about 6.0 mg / dL, about 5.0 mg / dL to about 6.0 mg / dL, about 1.0 mg / dL to about 5.0 mg / dL, about 2.decrease (e.g., from about 0 mg / dL to about 5.0 mg / dL, from about 3.0 mg / dL to about 5.0 mg / dL, from about 4.0 mg / dL to about 5.0 mg / dL, from about 1.0 mg / dL to about 4.0 mg / dL, from about 2.0 mg / dL to about 4.0 mg / dL, from about 3.0 mg / dL to about 4.0 mg / dL, from about 1.0 mg / dL to about 3.0 mg / dL, from about 2.0 mg / dL to about 3.0 mg / dL, or from about 1.0 mg / dL to about 2.0 mg / dL). For example, total bilirubin can be reduced by at least 70% (e.g., approximately 99%) after subcutaneous administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 24 weeks. In some embodiments, the total bilirubin level decreases by about 3.0 mg / dL, about 4.0 mg / dL, about 5.0 mg / dL, about 6.0 mg / dL, about 7.0 mg / dL, about 8.0 mg / dL, or about 9.0 mg / dL from baseline after subcutaneous administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. For example, total bilirubin can be reduced by at least 70% (e.g., approximately 99%) after subcutaneous administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 24 weeks..

[0101] In some embodiments, serum alkaline phosphatase (ALP) levels are improved after subcutaneous administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, ALP levels decrease after subcutaneous administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, ALP levels are reduced from baseline by about 50 U / L to about 175 U / L, about 50 U / L to about 150 U / L, about 50 U / L to about 125 U / L, about 50 U / L to about 100 U / L, about 50 U / L to about 75 U / L, about 75 U / L to about 175 U / L, about 75 U / L to about 150 U / L, about 75 U / L to about 125 U / L, about 75 U / L to about 100 U / L, about 100 U / L to about 175 U / L, about 100 U / L to about 150 U / L, about 100 U / L to about 125 U / L, about 125 U / L to about 175 U / L, about 125 U / L to about 150 U / L, or about 150 U / L to about 175 U / L after subcutaneous administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. For example, ALP levels can be reduced by approximately 50%, approximately 60% or approximately 70% after subcutaneous administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 24 weeks.

[0102] In some embodiments, after subcutaneous administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject shows a reduction in the relative mRNA expression of kidney injury molecule-1 (KIM-1). In some embodiments, the subject shows a reduction in the relative mRNA expression of urinary KIM-1 between about 5% and about 100%, such as between about 10% and about 100%, or such as between about 15% and about 100%. In some embodiments, the subject shows a reduction in the relative mRNA expression of urinary KIM-1 of at least 50% (e.g., 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 some embodiments, the subject shows a reduction in the relative mRNA expression of urinary KIM-1 of at least 60%, at least 70%, at least 80%, or at least 90%. In some embodiments, after subcutaneous administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject shows a reduction in the relative mRNA expression of urinary KIM-1 between about 50% and about 95% (e.g., between about 50% and about 90%, between about 50% and about 85%, between about 50% and about 80%, between about 50% and about 75%, between about 50% and about 70%, between about 50% and about 65%, between about 50% and about 60%, between about 50% and about 55%, between about 55% and about 95%, between about 55% and about 90%, between about 55% and about 85%, between about 55% and about 80%, between about 55% and about 75%, between about 55% and about 70%, between about 55% and about 65%, between about 55% and about 60%, between about 60% and about 95%, between about 60% and about 90%, between about 60% and about 85%, between about 60% and about 80%, between about 60% and about 75%, between about 60% and about 70%, between about 60% and about 65%, between about 65% and about 95%, between about 65% and about 90%, between about 65% and about 85%, between about 65% and about 80%, between about 65% and about 75%, between about 65% and about 70%, between about 70% and about 95%, between about 70% and about 90%, between about 70% and about 85%, between about 70% and about 80%, between about 70% and about 75%, between about 75% and about 95%, between about 75% and about 90%, between about 75% and about 85%, between about 75% and about 80%, between about 80% and about 95%, between about 80% and about 90%, between about 80% and about 85%, between about 85% and about 95%, between about 85% and about 90%, or between about 90% and about 95%).

[0103] In some embodiments, after subcutaneous administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject shows a reduction in the relative mRNA expression of lipocalin-2 (LCN2; also known as neutrophil gelatinase-associated lipocalin, or NGAL). In some embodiments, the subject shows a reduction in the relative mRNA expression of LCN2 between about 5% and about 100%, such as between about 10% and about 100%, or such as between about 15% and about 100%. In some embodiments, after subcutaneous administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject shows a reduction in the relative mRNA expression of LCN2 of about 50% to about 100% (e.g., about 50% to about 95%, about 50% to about 90%, about 50% to about 85%, about 50% to about 80%, about 50% to about 75%, about 50% to about 70%, about 50% to about 65%, about 50% to about 60%, about 50% to about 55%, about 55% to about 100%, about 55% to about 95%, about 55% to about 90%, about 55% to about 85%, about 55% to about 80%, about 55% to about 75%, about 55% to about 70%, about 55% to about 65%, about 55% to about 60%, about 60% to about 100%, about 60% to about 95%, about 60% to about 90%, about 60% to about 85%, about 60% to about 80%, about 60% to about 75%, about 60% to about 70%, about 60% to about 65%, about 65% to about 95%, about 65% to about 100%, about 65% to about 95%, about 65% to about 90%, about 65% to about 85%, about 65% to about 80%, about 65% to about 75%, about 65% to about 70%, about 70% to about 100%, about 70% to about 95%, about 70% to about 90%, about 70% to about 85%, about 70% to about 80%, about 70% to about 75%, about 75% to about 100%, about 75% to about 95%, about 75% to about 90%, about 75% to about 85%, about 80% to about 100%, about 80% to about 95%, about 80% to about 90%, about 80% to about 85%, about 85% to about 95%, about 85% to about 90%, about 90% to about 100%, about 90% to about 95%, or about 95% to about 100%). In some embodiments, the subject shows a reduction in the relative mRNA expression of LCN2 of at least about 50% (e.g., at least about 55%; at least about 60; at least about 65%; at least about 70%; at least about 75%; at least about 80%; at least about 85%; at least about 90%; or at least about 95%).In some embodiments, the subject exhibits a reduction in relative mRNA expression of LCN2 of at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0104] Formulation Subcutaneous administration of the ASBT inhibitor according to the present invention requires a liquid aqueous formulation. Such a formulation may include solubilizing and stabilizing excipients, such as salts (e.g., physiological saline), buffers, surfactants, co-solvents, antioxidants, and preservatives, in addition to the ASBT inhibitor.

[0105] Examples of buffers include salts such as phosphates, citrates, acetates, gluconates, lactates, tartrates, aspartates, glutamates, and phthalates, or their corresponding acid forms, as well as histidine or tris (tris (hydroxymethyl) aminomethane). The pH of the liquid formulation is in the range of about 4 to about 9, more preferably in the range of about 5 to about 8, and even more preferably in the range of about 6 to 7.

[0106] The surfactant may be a cationic surfactant, an anionic surfactant, or a non-ionic surfactant. Examples of cationic surfactants include, but are not limited to, cetyltrimethylammonium bromide (cetrimonium bromide) and cetylpyridinium chloride. Examples of anionic surfactants include, but are not limited to, sodium dodecyl sulfate (sodium lauryl sulfate) and ammonium dodecyl sulfate (ammonium lauryl sulfate). Examples of non-ionic surfactants include, but are not limited to, glycerol monooleate, glycerol monostearate, polyoxyl castor oil (Cremophor EL), poloxamers (e.g., poloxamer 407 or 188), polysorbate 80, and sorbitan esters (Tween). In a preferred embodiment, the surfactant is a cationic surfactant.

[0107] Examples of suitable co-solvents include, but are not limited to, ethanol, propylene glycol, polyethylene glycol 400 (PEG400), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), and N,N-dimethylacetamide (DMA).

[0108] Examples of suitable antioxidants include, but are not limited to, butylated hydroxytoluene (BHT), ascorbyl palmitate, propyl gallate, and ascorbic acid, and combinations thereof.

[0109] Examples of suitable preservatives include, but are not limited to, phenol, benzyl alcohol, methylparaben, ethylparaben, propylparaben, ethylenediaminetetraacetic acid (EDTA), potassium sorbate, and sodium benzoate, and combinations thereof.

[0110] In some embodiments, the concentration of the ASBT inhibitor in the liquid formulation is from about 0.001 to about 30 mg / mL. In some embodiments, the concentration of the ASBT inhibitor is from about 0.01 to about 10 mg / mL, such as from about 0.01 to about 1 mg / mL, from about 0.01 to about 2 mg / mL, from about 0.01 to about 3 mg / mL, from about 0.01 to about 4 mg / mL, from about 0.01 to about 5 mg / mL, from about 0.01 to about 6 mg / mL, from about 0.01 to about 7 mg / mL, from about 0.01 to about 8 mg / mL, from about 0.01 to about 9 mg / mL, from about 1 to about 2 mg / mL, from about 1 to about 3 mg / mL, from about 1 to about 4 mg / mL, from about 1 to about 5 mg / mL, from about 1 to about 6 mg / mL, from about 1 to about 7 mg / mL, from about 1 to about 8 mg / mL, from about 1 to about 9 mg / mL, from about 1 to about 10 mg / mL, from about 2 to about 3 mg / mL, from about 2 to about 4 mg / mL, from about 2 to about 5 mg / mL, from about 2 to about 6 mg / mL, from about 2 to about 7 mg / mL, from about 2 to about 8 mg / mL, from about 2 to about 9 mg / mL, from about 2 to about 10 mg / mL, from about 3 to about 4 mg / mL, from about 3 to about 5 mg / mL, from about 3 to about 6 mg / mL, from about 3 to about 7 mg / mL, from about 3 to about 8 mg / mL, from about 3 to about 9 mg / mL, from about 3 to about 10 mg / mL about 4 to about 5 mg / mL, about 4 to about 6 mg / mL, about 4 to about 7 mg / mL, about 4 to about 8 mg / mL, about 4 to about 9 mg / mL, about 4 to about 10 mg / mL, about 5 to about 6 mg / mL, about 5 to about 7 mg / mL, about 5 to about 8 mg / mL, about 5 to about 9 mg / mL, about 5 to about 10 mg / mL, about 6 to about 7 mg / mL, about 6 to about 8 mg / mL, about 6 to about 9 mg / mL, about 6 to about 10 mg / mL, about 7 to about 8 mg / mL, about 7 to about 9 mg / mL, about 7 to about 10 mg / mL, about 8 to about 9 mg / mL, about 8 to about 10 mg / mL, or about 9 to about 10 mg / mL. In some embodiments, the concentration of the ASBT inhibitor in the liquid formulation is about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1.0 mg / mL, about 1.2 mg / mL, about 1.4 mg / mL, about 1.6 mg / mL, about 1.8 mg / mL or about 2.0 mg / mL.

[0111] Dosage and Administration Frequency The ASBT inhibitor is typically administered to warm-blooded animals such as humans at a dosage in the range of about 0.1 to about 1000 μg / kg / day, for example about 1 μg / kg / day to about 1000 μg / kg / day, or for example about 10 μg / kg / day to about 1000 μg / kg / day. In some embodiments, the ASBT inhibitor is administered at a dosage of about 20 μg / kg / day, about 40 μg / kg / day, about 60 μg / kg / day, about 80 μg / kg / day, about 100 μg / kg / day, about 120 μg / kg / day, about 140 μg / kg / day, about 160 μg / kg / day, about 180 μg / kg / day, about 200 μg / kg / day, about 300 μg / kg / day, about 400 μg / kg / day, about 500 μg / kg / day, about 600 μg / kg / day, about 700 μg / kg / day, about 800 μg / kg / day, about 900 μg / kg / day, or about 1000 μg / kg / day.

[0112] In some embodiments, the ASBT inhibitor is administered at a dose of about 20 to about 800 μg / kg / day. For example, about 20 to about 600 μg / kg / day, about 20 to about 400 μg / kg / day, about 20 to about 200 μg / kg / day, about 20 to about 180 μg / kg / day, about 20 to about 160 μg / kg / day, about 20 to about 140 μg / kg / day, about 20 to about 120 μg / kg / day, about 20 to about 100 μg / kg / day, about 20 to about 80 μg / kg / day, about 20 to about 60 μg / kg / day, about 20 to about 40 μg / kg / day, about 40 to about 800 μg / kg / day, about 40 to about 600 μg / kg / day, about 40 to about 400 μg / kg / day, about 40 to about 200 μg / kg / day, about 40 to about 180 μg / kg / day, about 40 to about 160 μg / kg / day, about 40 to about 140 μg / kg / day, about 40 to about 120 μg / kg / day, about 40 to about 100 μg / kg / day, about 40 to about 80 μg / kg / day, about 40 to about 60 μg / kg / day, about 60 to about 800 μg / kg / day, about 60 to about 600 μg / kg / day, about 60 to about 400 μg / kg / day, about 60 to about 200 μg / kg / day, about 60 to about 180 μg / kg / day, about 60 to about 160 μg / kg / day, about 60 to about 140 μg / kg / day, about 60 to about 120 μg / kg / day, about 60 to about 100 μg / kg / day, about 60 to about 80 μg / kg / day, about 80 to about 800 μg / kg / day, about 80 to about 600 μg / kg / day, about 80 to about 400 μg / kg / day, about 80 to about 200 μg / kg / day, about 80 to about 180 μg / kg / day, about 80 to about 160 μg / kg / day, about 80 to about 140 μg / kg / day, about 80 to about 120 μg / kg / day, about 80 to about 100 μg / kg / day, about 100 to about 800 μg / kg / day, about 100 to about 600 μg / kg / day, about 100 to about 400 μg / kg / day, about 100 to about 200 μg / kg / day, about 100 to about 180 μg / kg / day, about 100 to about 160 μg / kg / day, about 100 to about 140 μg / kg / day, about 100 to about 120 μg / kg / day, about 120 to about 800 μg / kg / day, about 120 to about 600 μg / kg / day, about 120 to about 400 μg / kg / day, about 120 to about 200 μg / kg / day, about 120 to about 180 μg / kg / day, about 120 to about 160 μg / kg / day, about 120 to about 140 μg / kg / day, about 140 to about 800 μg / kg / day, about 140 to about 600 μg / kg / day,It is odevipibat or a pharmaceutically acceptable salt thereof at a dose of about 140 to about 400 μg / kg / day, about 140 to about 200 μg / kg / day, about 140 to about 180 μg / kg / day, about 140 to about 160 μg / kg / day, about 160 to about 800 μg / kg / day, about 160 to about 600 μg / kg / day, about 160 to about 400 μg / kg / day, about 160 to about 200 μg / kg / day, about 160 to about 180 μg / kg / day, about 180 to about 800 μg / kg / day, about 180 to about 600 μg / kg / day, about 180 to about 400 μg / kg / day, about 180 to about 200 μg / kg / day, about 200 to about 800 μg / kg / day, about 200 to about 600 μg / kg / day, about 200 to about 400 μg / kg / day, about 400 to about 800 μg / kg / day, about 400 to about 600 μg / kg / day, or about 600 to about 800 μg / kg / day.

[0113] In some embodiments, the ASBT inhibitor is administered as a unit dose in the range of about 1 μg to about 100 mg, such as about 10 μg to about 10 mg, such as about 100 μg to about 2000 μg, or such as about 200 μg to about 1500 μg. In some embodiments, the ASBT inhibitor is about 10 μg to about 9 mg, about 10 μg to about 8 mg, about 10 μg to about 7 mg, about 10 μg to about 6 mg, about 10 μg to about 5 mg, about 10 μg to about 4 mg, about 10 μg to about 3 mg, about 10 μg to about 2 mg, about 10 μg to about 1 mg, about 10 μg to about 800 μg, about 10 μg to about 600 μg, about 10 μg to about 400 μg, about 10 μg to about 200 μg, about 10 μg to about 100 μg, about 10 μg to about 50 μg, about 50 μg to about 10 mg, about 50 μg to about 9 mg, about 50 μg to about 8 mg, about 50 μg to about 7 mg, about 50 μg to about 6 mg, about 50 μg to about 5 mg, about 50 μg to about 4 mg, about 50 μg to about 3 mg, about 50 μg to about 2 mg, about 50 μg to about 1 mg, about 50 μg to about 800 μg, about 50 μg to about 600 μg, about 50 μg to about 400 μg, about 50 μg to about 200 μg, about 50 μg to about 100 μg, about 100 μg to about 10 mg, about 100 μg to about 9 mg, about 100 μg to about 8 mg, about 100 μg to about 7 mg, about 100 μg to about 6 mg, about 100 μg to about 5 mg, about 100 μg to about 4 mg, about 100 μg to about 3 mg, about 100 μg to about 2 mg, about 100 μg to about 1 mg, about 100 μg to about 800 μg, about 100 μg to about 600 μg, about 100 μg to about 400 μg, About 100 μg to about 200 μg, about 200 μg to about 10 mg, about 200 μg to about 9 mg, about 200 μg to about 8 mg, about 200 μg to about 7 mg, about 200 μg to about 6 mg, about 200 μg to about 5 mg, about 200 μg to about 4 mg, about 200 μg to about 3 mg, about 200 μg to about 2 mg, about 200 μg to about 1 mg, about 200 μg to about 800 μg, about 200 μg to about 600 μg, about 200 μg to about 400 μg, about 200 μg to about 10 mg, about 200 μg to about 9 mg, about 400 μg to about 8 mg, about 400 μg to about 7 mg, about 400 μg to about 6 mg, about 400 μg to about 5 mg, about 400 μg to about 4 mg, about 400 μg to about 3 mg, about 400 μg to about 2 mg, about 400 μg to about 1 mg, about 400 μg to about 800 μg, about 400 μg to about 600 μg, about 600 μg to about 10 mg, about 600 μg to about 9 mg, about 600 μg to about 8 mg, about 600 μg to about 7 mg, about 600 μg to about 6 mg, about 600 μg to about 5 mg, about 600 μg to about 4 mg, about 600 μg to about 3 mg, about 600 μg to about 2 mg, about 600 μg to about 1 mg, about 600 μg to about 800 μg About 800 μg to about 10 mg, about 800 μg to about 9 mg, about 800 μg to about 8 mg, about 800 μg to about 7 mg, about 800 μg to about 6 mg, about 800 μg to about 5 mg, about 800 μg to about 4 mg, about 800 μg to about 3 mg, about 800 μg to about 2 mg, about 800 μg to about 1 mg, about 1 mg to about 10 mg, about 1 mg to about 9 mg, about 1 mg to about 8 mg, about 1 mg to about 7 mg, about 1 mg to about 6 mg, about 1 mg to about 5 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, about 1 mg to about 2 mg, about 2 mg to about 10 mg, about 2 mg to about 9 mg, about 2 mg to about 8 mg, about 2 mg to about 7 mg, about 2 mg to about 6 mg, about 2 mg to about 5 mg, about 2 mg to about 4 mg, about 2 mg to about 3 mg, about 3 mg to about 10 mg It is administered as a unit dose in the range of about 3 mg to about 10 mg, about 3 mg to about 9 mg, about 3 mg to about 8 mg, about 3 mg to about 7 mg, about 3 mg to about 6 mg, about 3 mg to about 5 mg, about 3 mg to about 4 mg, about 4 mg to about 10 mg, about 4 mg to about 9 mg, about 4 mg to about 8 mg, about 4 mg to about 7 mg, about 4 mg to about 6 mg, about 4 mg to about 5 mg, about 5 mg to about 10 mg, about 5 mg to about 9 mg, about 5 mg to about 8 mg, about 5 mg to about 7 mg, about 5 mg to about 6 mg, about 6 mg to about 10 mg, about 6 mg to about 9 mg, about 6 mg to about 8 mg, about 6 mg to about 7 mg, about 7 mg to about 10 mg, about 7 mg to about 9 mg, about 7 mg to about 8 mg, about 8 mg to about 10 mg, about 8 mg to about 9 mg, or about 9 mg to about 10 mg. In some embodiments, the ASBT inhibitor is administered as a unit dose of about 100 μg, about 200 μg, about 300 μg, about 400 μg, about 500 μg, about 600 μg, about 700 μg, about 800 μg, about 900 μg, about 1000 μg, about 1100 μg, about 1200 μg, about 1300 μg, about 1400 μg, about 1500 μg, about 1600 μg, about 1700 μg, about 1800 μg, about 1900 μg, or about 2000 μg. The dosing frequency can vary from once or twice a week to once or multiple times a day, such as twice or three times a day. In some embodiments, the ASBT inhibitor is administered once a day. The dosing frequency can further be kept constant or variable during the treatment period. Several factors, such as the severity of the condition being treated, the treatment period, and the age, weight, gender, diet, and general medical condition of the patient being treated, can affect the dosing frequency and effective amount of the formulation to be used for a particular treatment.

[0114] As used herein, the terms "treatment", "treating", and "treatment" refer to the regression, alleviation, delay in the onset, or inhibition of progression of a disease or disorder as described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual (e.g., taking into account a medical history of symptoms and / or genetic or other susceptibility factors) prior to the onset of symptoms. Treatment may also be continued after symptoms have resolved, for example, to prevent or delay recurrence.

[0115] As used herein, the term "about" refers to a value or parameter in the present specification that includes (and describes) embodiments directed to the value or parameter itself. For example, a description referring to "about 20" includes a description of "20". Numerical ranges include the numbers defining the range. Generally speaking, the term "about" refers to either the value indicated by the variable, all values within the experimental error of the value indicated by the variable (e.g., within the 95% confidence interval of the mean), or within 10 percent of the value indicated by the variable, whichever is greater.

[0116] The present invention will now be described by way of the following examples, which in no way limit the present invention. All cited documents and references are incorporated by reference.

Examples

[0117] (Example 1) Plasma concentration after subcutaneous administration Erovixibat was administered to male C57BL / 6 mice (n = 5) as a subcutaneous injection at a dose of 3 or 10 mg / kg, or as an intravenous injection at a dose of 1 mg / kg (single injection), or as a repeated subcutaneous injection at a dose of 1 mg / kg on days 1 and 5. Erovixibat was formulated in 70% PEG400; 10% ethanol; and 20% water and administered subcutaneously at a volume of 5 mL / kg or intravenously at a volume of 1 mL / kg. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after subcutaneous administration, and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after intravenous administration. Blood samples were taken from the saphenous vein. 0.2% EDTA was used as an anticoagulant. Samples were analyzed using an LC-MS / MS system by a discovery grade biological assay developed to estimate erovixibat in plasma.

[0118] Results for single subcutaneous (3 or 10 mg / kg) and intravenous (1 mg / kg) administrations are shown in Figure 1, and results for repeated subcutaneous administration (1 mg / kg on days 1 and 5) are shown in Figure 2.

[0119] (Example 2) In vivo animal model of cholestatic disease Long-term feeding of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was used as an in vivo model for cholestatic liver injury. Long-term feeding of DDC results in the formation of intraductal porphyrin plugs that lead to bile duct obstruction, which contributes to damage of the biliary epithelium. The time course of the DDC model typically ranges from 1 to 6 weeks depending on the severity of cholangiopathy required for the study. Long-term feeding of DDC in mice reproduces the major histopathological hallmarks of human cholestatic disease, including (1) remodeling of the biliary compartment that generates a cholangiolar response, (2) pericholangiolar fibrosis, and (3) inflammatory infiltrates (Mariotti et al., Biochim Biophys Acta Mol Basis Dis 2018, Vol. 1864, pp. 1254-1261; Pose et al., Methods Mol. Biol. 2019, Vol. 1981, pp. 249-257).

[0120] Eight-week-old male C57BL / 6J WT mice were used. After completion of the quarantine and acclimation period, the animals were randomly divided into experimental groups based on body weight (n = 7 - 9 / group). The animals were fed a solid diet (control diet), or a solid diet + 0.1% DDC (DDC diet) for 14 days as shown in Table 1, and were treated once daily with vehicle (s.c.), or the ASBT inhibitor elobixibat at doses of 0.3, 1.0 or 3.0 mg / kg (s.c.). The animals were weighed on days 7, 11 and 14. Blood samples were collected on day 7. On day 11, the animals were transferred to individual cages with wire bottoms for feces collection. Blood, urine, tissue samples and 3-day fecal samples were collected on day 14.

[0121]

Table 1

[0122] Endpoints measured at the end of the study included bile acid excretion in feces, bile acid concentrations and composition in urine and serum, and serum chemistry values reflecting liver status.

[0123] Blood sample analysis showed a statistically significant reduction in serum bile acids (Figure 3) and serum total bilirubin (Figure 4) with daily s.c. administration of elobixibat. The levels were reduced at the lowest dose and no further reduction was observed at higher doses. A dose-dependent trend of reduction in serum alkaline phosphatase (ALP) levels was observed with daily s.c. administration of elobixibat (Figure 5).

[0124] Figures 6 and 7 show the mRNA expression of KIM-1 (kidney injury molecule-1) and LCN2 (lipocalin-2), markers of proximal renal tubular cell injury. The mRNA expression of KIM-1 and LCN2 was induced in DDC cholestatic mice. The mRNA expression of KIM-1 and LCN2 was observed to be reduced in DDC cholestatic mice treated with s.c. elobixibat compared to vehicle.

Claims

1. A pharmaceutical product administered subcutaneously for the treatment of liver or kidney disease or disorder, comprising an ASBT inhibitor or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical product according to claim 1, wherein the ASBT inhibitor does not inhibit renal ASBT at a clinically relevant level after oral administration.

3. The pharmaceutical product according to claim 1, wherein less than 10% of the ASBT inhibitor is absorbed systemically after oral administration.

4. The pharmaceutical product according to claim 1, wherein the ASBT inhibitor is selected from the group consisting of elobixibat, odebixibat, malalixibat, vorixibat, and linelixibat.

5. The pharmaceutical product according to claim 1, wherein the ASBT inhibitor is elobixibat.

6. The pharmaceutical product according to claim 1, wherein the disease or disorder of the liver or kidney is a bile acid-dependent disease or disorder.

7. The pharmaceutical product according to claim 1, wherein the disease or disorder of the liver or kidney includes a disorder or defect of bile flow.

8. The pharmaceutical product according to claim 1, wherein the disease or disorder of the liver or kidney includes cholestasis.

9. The pharmaceutical product according to claim 1, wherein the liver disease or disorder is PFIC type 2.

10. A pharmaceutical product for use according to claim 1, wherein the liver disease or disorder includes BSEP3 deficiency.

11. The pharmaceutical product according to claim 1, wherein the disease or disorder of the liver or kidney includes biliary obstruction.

12. The pharmaceutical product according to claim 1, wherein the liver disease or disorder is biliary atresia, including biliary atresia after Kasai surgery and biliary atresia after liver transplantation.

13. The pharmaceutical product according to claim 1, wherein the liver disease or disorder is acute cholangitis or obstructive cholangitis.

14. The pharmaceutical product according to claim 1, wherein the liver disease or disorder is a malignant biliary obstruction caused by, for example, bile duct cancer, pancreatic cancer, gallbladder cancer, or colon cancer.

15. The pharmaceutical product according to claim 1, wherein the kidney disease or disorder is selected from the group consisting of biliary nephropathy, chronic nephropathy, hyperbilirubinemia, renal dysfunction with obstructive jaundice, age-related impairment of mitochondrial function in the kidney, renal inflammation, acute kidney injury (AKI), renal ischemia / reperfusion injury (IRI), chronic kidney disease (CKD), polycystic kidney disease (PKD), joint contracture-renal dysfunction-cholestasis (ARC) syndrome, familial lecithin cholesterol acyltransferase (LCAT) deficiency, chronic renal failure, end-stage renal disease (ESRD), proximal tubular injury in the kidney, type 1 hepatorenal syndrome, type 2 hepatorenal syndrome, and acute exacerbation of chronic liver disease.

16. The pharmaceutical product according to claim 1, wherein the kidney disease or disorder is biliary nephropathy.

17. The pharmaceutical product according to claim 1, which is administered to a patient who is also receiving treatment with an orally administered non-systemically absorbed ASBT inhibitor.

18. The pharmaceutical agent according to claim 1, administered to a patient who does not respond to treatment with an orally administered non-systemically absorbed ASBT inhibitor.

19. The pharmaceutical product according to claim 1, administered to a patient who is intolerant to treatment with orally administered non-systemically absorbed ASBT inhibitors.

20. The pharmaceutical product according to claim 1, which is administered once a day.

21. The pharmaceutical agent according to claim 1, wherein the target of administration of the pharmaceutical agent exhibits a reduction in serum bile acid concentration after subcutaneous administration of the pharmaceutical agent.

22. The pharmacopoeia according to claim 21, wherein the reduction in serum bile acid concentration is at least 60%, at least 70%, at least 80%, or at least 90% compared to baseline.

23. The pharmaceutical agent according to claim 1, wherein the target of administration of the pharmaceutical agent exhibits an increase in urinary bile acids after subcutaneous administration of the pharmaceutical agent.

24. The pharmacopoeia according to claim 23, wherein the increase in urinary bile acids is at least 60%, at least 70%, at least 80%, or at least 90% compared to baseline.

25. The pharmaceutical agent according to claim 1, wherein the target of administration of the pharmaceutical agent shows improvement in liver parameters after subcutaneous administration of the pharmaceutical agent.

26. The pharmaceutical product according to claim 25, wherein the liver parameter is selected from the group consisting of serum total bilirubin level, serum alkaline phosphatase (ALP) level, serum alanine aminotransferase (ALT) level, and serum aspartate aminotransferase (AST) level.

27. The pharmacopoeia according to claim 25, wherein improvement in liver parameters occurs after subcutaneous administration of the pharmacopoeia for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, or at least 48 weeks.

28. The pharmaceutical agent according to claim 1, wherein the target of administration of the pharmaceutical agent exhibits a reduction in the relative mRNA expression of kidney damage molecule-1 (KIM-1) after subcutaneous administration of the pharmaceutical agent.

29. The pharmaceutical product according to claim 28, wherein the relative reduction in KIM-1 mRNA expression is at least 60%, at least 70%, at least 80%, or at least 90%.

30. The pharmaceutical agent according to claim 1, wherein the target of administration of the pharmaceutical agent exhibits a reduction in the relative mRNA expression of lipocalin-2 (LCN2) after subcutaneous administration of the pharmaceutical agent.

31. The pharmaceutical product according to claim 30, wherein the relative reduction in LCN2 mRNA expression is at least 60%, at least 70%, at least 80%, or at least 90%.

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