REMOGLIFLOZIN
5-METHYL-4-[4-(1-METHYLETHOXY)BENZYL]-1-(1-METHYLETHYL)-1H-PYRAZOL-3-YL 6-O-(ETHOXYCARBONYL)-?-D-GLUCOPYRANOSIDE,
ETHYL [(2R,3S,4S,5R,6S)-3,4,5-TRIHYDROXY-6-[5-METHYL-1-PROPAN-2-YL-4-[(4-PROPAN-2-YLOXYPHENYL)METHYL]PYRAZOL-3-YL]OXY-OXAN-2-YL]METHYL CARBONATE
REMOGLIFLOZIN ETABONATE
PHASE II
A SGLT-2 ANTAGONIST POTENTIALLY FOR THE TREATMENT OF TYPE 2 DIABETES, NON-ALCOHOLIC STEATOHEPATITIS (NASH), OBESITY.
REMOGLIFLOZIN ETABONATE IS A PROPOSED DRUG OF THE GLIFLOZIN CLASS FOR THE TREATMENT OF NON-ALCOHOLIC STEATOHEPATITIS (βNASHβ) AND TYPE 2 DIABETES. REMOGLIFLOZIN IS BEING DEVELOPED BY AVOLYNT, INC.
REMOGLIFLOZIN ETABONATE, ALSO KNOWN AS GSK 189075A OR GSK 189075, IS A SGLT2 INHIBITOR UNDER DEVELOPMENT FOR THE TREATMENT OF TYPE 2 DIABETES. REMOGLIFLOZIN ETABONATE IS A PRO-DRUG OF REMOGLIFLOZIN. REMOGLIFLOZIN INHIBITS THE SODIUM-GLUCOSE TRANSPORT PROTEINS (SGLT), WHICH ARE RESPONSIBLE FOR GLUCOSE REABSORPTION IN THE KIDNEY. BLOCKING THIS TRANSPORTER CAUSES BLOOD GLUCOSE TO BE ELIMINATED THROUGH THE URINE. REMOGLIFLOZIN IS SELECTIVE FOR SGLT2.
REMOGLIFLOZIN ETABONATE ALSO KNOWN AS 5-METHYL-4-[4-(1-METHYLETHOXY)BENZYL]-1-(1- METHYLETHYL)-1H-PYRAZOL-3-YL 6-0-(ETHOXYCAR ONYL)-?-D-GLUCOPYRANOSIDE OF THE FOLLOWING FORMULA
(Β«):
(I)
ANOTHER NOMENCLATURE CONVENTION PROVIDES THIS MOLECULE AS 3-(6-0-ETHOXYCARBONYL-.BETA.-D- GLUCOPYRANOSYLOXY)-4-[(4-ISOPROPOXYPHENYL)METHYL]-1-ISOPROPYL-5-METHYLPYRAZOLE. REMOGLIFLOZIN ETABONATE IS ALSO KNOWN AS GSK 189075 OR KGT-1681. SALTS OF COMPOUNDS OF FORMULA (I) ARE USEFUL AS THE ACTIVE INGREDIENT IN THE PHARMACEUTICAL PRESENTATION OF THE INVENTION. SUCH SALTS MAY BE AS DESCRIBED IN US PATENT 7,084,123 ISSUED AUGUST 1, 2006, HEREIN INCORPORATED BY REFERENCE. EXAMPLES OF SUCH SALTS INCLUDE ACID ADDITION SALTS WITH MINERAL ACIDS SUCH AS HYDROCHLORIC ACID, HYDROBROMIC ACID, HYDROIODIC ACID, SULFURIC ACID, NITRIC ACID, PHOSPHORIC ACID AND THE LIKE, ACID ADDITION SALTS WITH ORGANIC ACIDS SUCH AS FORMIC ACID, ACETIC ACID,
METHANESULFONIC ACID, BENZENESULFONIC ACID, P-TOLUENESULFONIC ACID, PROPIONIC ACID, CITRIC ACID, SUCCINIC ACID, TARTARIC ACID, FUMARIC ACID, BUTYRIC ACID, OXALIC ACID, MALONIC ACID, MAIEIC ACID, LACTIC ACID, MALIC ACID, CARBONIC ACID, GLUTAMIC ACID, ASPARTIC ACID, ADIPIC ACID, OLEIC ACID, STEARIC ACID AND THE LIKE, AND SALTS WITH INORGANIC BASES SUCH AS A SODIUM SALT, A POTASSIUM SALT, A CALCIUM SALT, A MAGNESIUM SALT AND THE LIKE.
THE COMPOUNDS REPRESENTED BY THE ABOVE FORMULA (I) INCLUDE THEIR SOLVATES WITH PHARMACEUTICALLY ACCEPTABLE SOLVENTS SUCH AS ETHANOL AND WATER.
REMOGLIFLOZIN ETABONATE MAY BE PREPARED AS DESCRIBED IN US PATENTS 7,084,123 AND 7,375,087, IN PARTICULAR EXAMPLE 1 OF US PATENT 7,084,123, EACH HEREIN INCORPORATED BY REFERENCE.
REMOGLIFLOZIN ETABONATE IS THE PRO-DRUG OF REMOGLIFLOZIN (ALSO KNOWN AS GSK189074 OR KGT-1650).
REMOGLIFLOZIN ETABONATE HAS THE POTENTIAL TO BE USED AS MONOTHERAPY FOR THE TREATMENT OF T2DM. TO DATE, STUDIES HAVE ASSESSED THE EFFICACY, SAFETY AND TOLERABILITY UP TO 12 WEEKS, WITH VARYING EFFICACY SO THERE IS A NEED TO CHARACTERIZE THE PROFILE OF A NUMBER OF SELECTED FORMULATED DOSES OVER A 12-WEEK PERIOD. THE STUDY IS DESIGNED WITH A PLACEBO TREATMENT ARM TO ENABLE THE PROFILE OF THE DRUG TO BE FURTHER CHARACTERIZED AND FOR MAXIMAL GLYCEMIC EFFECT TO BE ACHIEVED. HOWEVER TO MINIMIZE THE TIME WHICH SUBJECTS MAY HAVE SUB-OPTIMAL GLYCEMIC CONTROL, THE DOUBLE BLIND STUDY MEDICATION HAS BEEN LIMITED TO 12 WEEKS DURATION. IN ADDITION, CRITERIA HAVE BEEN INCLUDED TO ALLOW THE INTRODUCTION OF RESCUE THERAPY AFTER 6 WEEKS FOR THOSE SUBJECTS WHO HAVE A HIGH FP.