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(12) Patent Application Publication (10) Pub. No.: US 2016/0184387 A1 Charmot Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0184387 A1 Charmot Et Al US 2016O184387A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0184387 A1 Charmot et al. (43) Pub. Date: Jun. 30, 2016 (54) COMPOUNDS AND METHODS FOR A 6LX3 L/7072 (2006.01) INHIBITING PHOSPHATE TRANSPORT A613 L/4525 (2006.01) A63L/382 (2006.01) (71) Applicants: Dominique CHARMOT, Campbell, CA A63L/27 (2006.01) (US); Jason G. LEWIS, Castro Valley, A613 L/42 (2006.01) CA (US); Jeffrey W. JACOBS, San A613 L/353 (2006.01) Mateo, CA (US); Ingrid A613 L/4439 (2006.01) LANGSETMO, Fremont, CA (US); A613 L/4045 (2006.01) Christopher RERAS, Belmont, CA A633/26 (2006.01) (US) A613 L/475 (2006.01) A613 L/352 (2006.01) (72) Inventors: Dominique Charmot, Campbell, CA A 6LX3L/95 (2006.01) (US); Jason G. Lewis, Castro Valley, CA A6II 45/06 (2006.01) (US); Jeffrey W. Jacobs, San Mateo, CA GOIN33/50 (2006.01) (US); Ingrid Langsetmo, Fremont, CA GOIN33/84 (2006.01) (US); Christopher Carreras, Belmont, A613 L/506 (2006.01) CA (US) (52) U.S. Cl. CPC ............... A61K 38/10 (2013.01); A61 K3I/506 (21) Appl. No.: 14/911,225 (2013.01); A61 K3I/4418 (2013.01); A61 K (22) PCT Filed: Aug. 8, 2014 31/7072 (2013.01);ER 2. A61 (2013.01); K31/4525 (2013.01);R E; (2013.01); A61 K3I/421 (2013.01); A61 K (86). PCT No.: PCT/US2O14/OSO290 3 1/353 (2013.01); A61 K3I/4439 (2013.01): S371 (c)(1), A6 IK3I/4045 (2013.01); A61K33/26 (2) Date: Feb. 9, 2016 (2013.01); A61 K3I/475 (2013.01); A61 K 31/352 (2013.01); A61K 31/195 (2013.01); Related U.S. Application Data A61K 45/06 (2013.01); G0IN33/5044 (60) Provisional application No. 61/936,715, filed on Feb. (2013.01); G0IN33/5038 (2013.01); G0IN 6, 2014, provisional application No. 61/864,215, filed 33/84 (2013.01) on Aug. 9, 2013. (57) ABSTRACT Publication Classification Provided are non-NHE3-binding agents having activity as phosphate transport/uptake inhibitors in the gastrointestinal (51) Int. Cl. tract, including in the Small intestine, methods for their use as A6 IK38/10 (2006.01) therapeutic or prophylactic agents, and related methods of A6 IK3I/448 (2006.01) drug discovery. Patent Application Publication Jun. 30, 2016 Sheet 1 of 55 US 2016/O184387 A1 -o- Wehicle ---- Linaclofide 0.1 mg/kg Sr. 2.0 --A-- Linaclofide 0.5 mg/kg 80 3 e 1.5 2 60 k .S 1.0 E. 40 3. s 0.5 E 20 C es 00 8 0 as ---- O 50 60 s s \s \s Time post-dose (min) SS & & N 1. FIG. 1A s' s S s S Š Patent Application Publication Jun. 30, 2016 Sheet 2 of 55 US 2016/O184387 A1 -e- Vehicle 1S --0-- NKH477 1 mg/kg 5 -i-o-- NKH477 5 mg/kg &S 100 -A- Moxonidine 2 mg/kg -v- Moxonidine 6 mg/kg 80– 2. O 1 5 1.O 0. 5 iii. .NS NS NS NS) NS 0. O Š N as sis KMa KNa RS SS. Time post-dose (min) s W. s W. S.S. S.SS NS QS FIG. 2A Patent Application Publication Jun. 30, 2016 Sheet 3 of 55 US 2016/O184387 A1 -o- Vehicle 2.5 --A-- BAY 60-6585 10 mg/kg ---- Up4U 15 mg/kg 2.0 15 1.0 0.5 30 60 Time post-dose (min) FIG 3 Patent Application Publication Jun. 30, 2016 Sheet 4 of 55 US 2016/O184387 A1 roso; & 3. s * *s sex a so - Yo & w Patent Application Publication Jun. 30, 2016 Sheet 5 of 55 US 2016/O184387 A1 FIG 4 (Continued) Patent Application Publication Jun. 30, 2016 Sheet 6 of 55 US 2016/O184387 A1 SS : s x. 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FIG 9B (Continued) Patent Application Publication Jun. 30, 2016 Sheet 20 of 55 US 2016/O184387 A1 s SS **************& ;: & % *******ºººººººººººººººræøø,^^^^^^^^^, FIG 9C (Continued) Patent Application Publication Jun. 30, 2016 Sheet 21 of 55 US 2016/O184387 A1 zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz FIG 9D Patent Application Publication Jun. 30, 2016 Sheet 22 of 55 US 2016/O184387 A1 FIG 9D (ContI nued) Patent Application Publication Jun. 30, 2016 Sheet 23 of 55 US 2016/O184387 A1 Patent Application Publication Jun. 30, 2016 Sheet 24 of 55 US 2016/O184387 A1 & sw'sssssssssssssssssssssssssss-NMSssssssssssssssssssssssssssssssssssms\ssw...,x*.*.*.*.*.*.*.*.*.*.*.*.xxxx&sssssssss FIG 9E (Continued) Patent Application Publication Jun. 30, 2016 Sheet 25 of 55 US 2016/O184387 A1 S S S S S S S S Patent Application Publication Jun. 30, 2016 Sheet 26 of 55 US 2016/O184387 A1 $ S &S S.S S. 8 assass---8----------------------------------------- · FIG 9F (Continued) Patent Application Publication Jun. 30, 2016 Sheet 27 of 55 US 2016/O184387 A1 FIG 9G Patent Application Publication Jun. 30, 2016 Sheet 28 of 55 US 2016/O184387 A1 ¿? ? 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Patent Application Publication Jun. 30, 2016 Sheet 30 of 55 US 2016/O184387 A1 xx-xxxxx.xxx:XXXXXXXXXXXXX-XXXX-XXXX-XXXX-XXXX-XXXXXXXXXXX-3&vv8.xxxxxxxxxxxxxx xxv-xxx-xx-xxx-xxxxv-xxxxxxxxxv-xxxx.xxxxxxx :::::-:-?????????zzzzzzzzzzzzzzz:::::::::::::zzzzzzzzzzzzzzzzzzzzzzzzz.&.* ×2×3×3×3×2×2×2×…×zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz….…….……ž FIG 9H (Continued) Patent Application Publication Jun. 30, 2016 Sheet 31 of 55 US 2016/O184387 A1 . .xxxxxx xxxx....... ... ... ... .Y.Y.S. !!!!!!!!!!!!!!!!!!!!!!!!!!!,,,,,,,,,,,,,,,,,,,,,,, $: : : ;&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& FIG 91 Patent Application Publication Jun. 30, 2016 Sheet 32 of 55 US 2016/O184387 A1 ***^^***^^***^^****-rzzzzzzzzzzzzzzzzzzzzz…:... ,'',***************************************************...*.*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)'.',', “;&#################??:.*?&&&&&&&&&&&&&~~~~~~~~~-***-**-*---------------------------- FIG 91 (Continued) Patent Application Publication Jun. 30, 2016 Sheet 33 of 55 US 2016/O184387 A1 sax-XXXXXaxxx............& FIG 9) Patent Application Publication Jun. 30, 2016 Sheet 34 of 55 US 2016/O184387 A1 ********&&&&&& FIG 9J (ContI nued) Patent Application Publication Jun. 30, 2016 Sheet 35 of 55 US 2016/O184387 A1 sesssssssssssssssss-3333333333333333333333333333-33s: Patent Application Publication Jun. 30, 2016 Sheet 36 of 55 US 2016/O184387 A1 &&&&&&&&&zººzzzzzzzzzzzzzzzzzzzzzzz&ºzzzzzz Patent Application Publication Jun. 30, 2016 Sheet 37 of 55 US 2016/O184387 A1 s&SSS3&ssssss-SSSSS3& %) ..yyySSSSSS... 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El,s $ & {{s- s: s are> ns ii.a -W a- is > eptaloprost (13) ONO-8815ly ciprosten is FA-2O62 aka EPaRAG FIG 13(Continued) Patent Application Publication Jun. 30, 2016 Sheet 45 of 55 US 2016/O184387 A1 Patent Application Publication Jun. 30, 2016 Sheet 46 of 55 US 2016/O184387 A1 | ÇIOIH s Patent Application Publication Jun.
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