JP-2022533251-A5 -

Dates

Publication Date

20230530

Application Date

20200521

Description

Effects on renal clearance of phosphorus and sodium: Tenapanol and sevelamer alone significantly reduced renal clearance of phosphorus, reflecting an appropriate renal response in the face of reduced intestinal phosphorus absorption. In combination with tenapanol, sevelamer further and dose-dependently reduced phosphorus clearance, and the reduction by combination was significantly greater than that of either equivalent doses of tenapanol or sevelamer alone. Tenapanol alone significantly reduced renal clearance of sodium, reflecting an appropriate renal response to conserve sodium in the face of reduced intestinal phosphorus absorption. Sevelamer alone did not affect renal sodium processing as it did not affect intestinal sodium absorption. Renal clearance of sodium was not significantly affected by sevelamer at 0.75% or 1.5% w/w when combined with tenapanol. However, compared to tenapanol alone, the combination with 3% w/w sevelamer resulted in significantly higher sodium renal clearance, reflecting a weakening of the sodium-lowering pharmacodynamic effect of tenapanol when combined with this high dose of sevelamer. The present invention provides, for example, the following items: (Item 1) A method for lowering serum phosphate in a patient, comprising administering an effective amount of an epithelial phosphate transport inhibitor in combination with a phosphate binder, wherein the amount of the phosphate binder administered is less than the amount administered as a monotherapy agent. (Item 2) The method according to item 1, wherein the phosphate binder is selected from the group consisting of sevelamer, lanthanum carbonate, calcium carbonate, calcium acetate, calcium acetate/magnesium carbonate, MCI-196, ferric citrate, sucrose iron hydroxyhydroxyhydroxide, iron magnesium carbonate, aluminum hydroxide, APS1585, SBR-759, and PA-21. (Item 3) The method according to item 1, wherein the epithelial phosphate transport inhibitor is a compound that lowers the pH of epithelial cells. (Item 4) The method according to item 3, wherein the compound is selected from the group consisting of NHE3 inhibitors, guanylate cyclase C receptor (GC-C) agonists, P2Y agonists, adenosine A2b receptor agonists, soluble guanylate cyclase agonists, adenylyl cyclase receptor agonists, imidazoline-1 receptor agonists, cholinergic agonists, prostaglandin EP4 receptor agonists, dopamine D1 agonists, melatonin receptor agonists, 5HT4 agonists, atrial natriuretic peptide receptor agonists, carbonic anhydrase inhibitors, phosphodiesterase inhibitors, and agonists that are downregulated in adenomas (DRA or SLC26A3). (Item 5) The epithelial phosphate transport inhibitor is an NHE3 inhibitor having the structure of formula (I) or (IX), During the ceremony, NHE is an NHE-bonded small molecule comprising (i) a heteroatom-containing moiety and (ii) a cyclic or heterocyclic skeleton or support moiety directly or indirectly bonded thereto, wherein the heteroatom-containing moiety is selected from substituted guanidinyl moieties and substituted heterocyclic moieties, which can optionally condense with the skeleton or support moiety to form a condensed bicyclic structure. Z is a portion having at least one site thereon for attachment to the NHE-binding small molecule, and the resulting NHE-Z molecule has overall physicochemical properties that make it substantially impermeable or substantially systemically bioavailable. The method according to any one of items 1 to 4, wherein E is an integer with a value of 1 or more. (Item 6) The compound is an oligomer, dendrimer, or polymer, and further, Z is a core portion having two or more portions thereon for attachment to a plurality of NHE-bonded small molecules, either directly or indirectly via a linking portion L, and the compound has the structure of formula (X), The method according to any one of items 1 to 4, wherein L is a bond or linker connecting the core to the NHE-binding small molecule, n is an integer of 2 or more, and each NHE-binding small molecule may be the same as or different from the others. (Item 7) The NHE-bound small molecule has the structure of formula (IV): or having its stereoisomer, prodrug, or pharmaceutically acceptable salt thereof, During the ceremony, Each R1 , R2 , R3 , R5 , and R9 is independently selected from H, halogen, -NR7 ( CO )R8 , -(CO)NR7R8 , -SO2 - NR7R8 , -NR7SO2R8, -NR7R8 , -OR7, -SR7, -O(CO)NR7R8, -NR7 ( CO ) OR8 , and -NR7SO2NR8 , wherein R7 and R8 are independently selected from H or a bond linking the NHE - bonded small molecule to L , provided that at least one of them is a bond linking the NHE - bonded small molecule to L. R4 is selected from H, C1 - C7 alkyl , or a bond that links the NHE-bonded small molecule to L. R6 is either absent or selected from H and C1 - C7 alkyl groups. The method according to item 6, wherein Ar1 and Ar2 independently represent an aromatic ring or a heteroaromatic ring. (Item 8) The aforementioned NHE-binding small molecule h