Discovery of a clinical candidate from the structurally unique dioxa-bicyclo[3.2.1]octane class of sodium-dependent glucose cotransporter 2 inhibitors.

Compound 4 (PF-04971729) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclinical evaluation, and human dose predictions related to 4. This compound demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It is currently in phase 2 clinical trials and is being evaluated for the treatment of type 2 diabetes.

[1]  Joshua J. Neumiller,et al.  Sodium-Glucose Co-Transport Inhibitors , 2010, Drugs.

[2]  Y. Koga,et al.  Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. , 2010, Journal of medicinal chemistry.

[3]  R. Henry,et al.  SGLT2 inhibition — a novel strategy for diabetes treatment , 2010, Nature Reviews Drug Discovery.

[4]  Vincent Mascitti,et al.  Stereoselective synthesis of a dioxa-bicyclo[3.2.1]octane SGLT2 inhibitor. , 2010, Organic letters.

[5]  S. Murray,et al.  Multiple‐Dose Pharmacokinetics and Pharmacodynamics of Sergliflozin Etabonate, a Novel Inhibitor of Glucose Reabsorption, in Healthy Overweight and Obese Subjects: A Randomized Double‐Blind Study , 2010, Journal of clinical pharmacology.

[6]  S. Murray,et al.  Single‐Dose Pharmacokinetics and Pharmacodynamics of Sergliflozin Etabonate, a Novel Inhibitor of Glucose Reabsorption, in Healthy Volunteers and Patients With Type 2 Diabetes Mellitus , 2010, Journal of clinical pharmacology.

[7]  Joshua J. Neumiller,et al.  Review of Medications Used in the Treatment of Diabetes Mellitus , 2010 .

[8]  Paolo Pozzilli,et al.  The A1C and ABCD of glycaemia management in type 2 diabetes: a physician's personalized approach , 2010, Diabetes/metabolism research and reviews.

[9]  Craig I Coleman,et al.  Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. , 2010, JAMA.

[10]  M. Leininger,et al.  Syntheses of C-5-spirocyclic C-glycoside SGLT2 inhibitors , 2010 .

[11]  H. Kakinuma,et al.  (1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol (TS-071) is a potent, selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes treatment. , 2010, Journal of medicinal chemistry.

[12]  T. Maurer,et al.  C-Aryl glycoside inhibitors of SGLT2: Exploration of sugar modifications including C-5 spirocyclization. , 2010, Bioorganic & medicinal chemistry letters.

[13]  S. Nair,et al.  Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus. , 2010, The Journal of clinical endocrinology and metabolism.

[14]  Jr . John R. White.  Apple Trees to Sodium Glucose Co-Transporter Inhibitors: A Review of SGLT2 Inhibition , 2010, Clinical Diabetes.

[15]  W. Washburn.  Evolution of sodium glucose co-transporter 2 inhibitors as anti-diabetic agents , 2009, Expert opinion on therapeutic patents.

[16]  Alan G. E. Wilson,et al.  Novel L-xylose derivatives as selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes. , 2009, Journal of medicinal chemistry.

[17]  Bill J Smith,et al.  Prediction of Human Pharmacokinetics From Preclinical Information: Comparative Accuracy of Quantitative Prediction Approaches , 2009, Journal of clinical pharmacology.

[18]  Ralph A. DeFronzo,et al.  From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus , 2009, Diabetes.

[19]  W. Washburn.  Development of the renal glucose reabsorption inhibitors: a new mechanism for the pharmacotherapy of diabetes mellitus type 2. , 2009, Journal of medicinal chemistry.

[20]  M. Majowicz,et al.  Inhibitors of the sodium glucose contrasport , 2009, Drugs of the Future.

[21]  W. Humphreys,et al.  Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. , 2008, Journal of medicinal chemistry.

[22]  C. Levetan.  Oral antidiabetic agents in type 2 diabetes , 2007, Current medical research and opinion.

[23]  A. Kalgutkar,et al.  Minimising the potential for metabolic activation in drug discovery , 2005, Expert opinion on drug metabolism & toxicology.

[24]  Ernesto Callegari,et al.  A comprehensive listing of bioactivation pathways of organic functional groups. , 2005, Current drug metabolism.

[25]  N. Lewis,et al.  Phlorizin: a review , 2005, Diabetes/metabolism research and reviews.

[26]  M. Hediger,et al.  The high affinity Na+/glucose cotransporter. Re-evaluation of function and distribution of expression. , 1994, The Journal of biological chemistry.

[27]  M. Hediger,et al.  The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. , 1994, The Journal of clinical investigation.

[28]  C. Warren,et al.  The allyl ether as a protecting group in carbohydrate chemistry. , 1974, Tetrahedron letters.

[29]  R. Schaffer.  Branched-chain Higher Sugars. III. A 4-C-(Hydroxymethyl)-pentose1 , 1959 .