Metabolic and Endocrine Diseases Research Unit

Anderson, United States

Metabolic and Endocrine Diseases Research Unit

Anderson, United States
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Miao Z.,Pfizer | Nucci G.,Clinical Pharmacology | Amin N.,Metabolic and Endocrine Diseases Research Unit | Sharma R.,Pfizer | And 5 more authors.
Drug Metabolism and Disposition | Year: 2013

The disposition of ertugliflozin (PF-04971729), an orally active selective inhibitor of the sodium-dependent glucose cotransporter 2, was studied after a single 25-μg oral dose of [14C]-ertugliflozin to healthy human subjects. Mass balance was achieved with approximately 91% of the administered dose recovered in urine and feces. The total administered radioactivity excreted in feces and urine was 40.9% and 50.2%, respectively. The absorption of ertugliflozin in humans was rapid with a Tmax at ̃1.0 hour. Of the total radioactivity excreted in feces and urine, unchanged ertugliflozin collectively accounted for ̃35.3% of the dose, suggestive of moderate metabolic elimination in humans. The principal biotransformation pathway involved glucuronidation of the glycoside hydroxyl groups to yield three regioisomeric metabolites, M4a, M4b, and M4c (̃39.3% of the dose in urine), of which M4c was the major regioisomer (̃31.7% of the dose). The structure of M4a and M4c were confirmed to be ertugliflozin -4-O-β- and -3-O-βglucuronide, respectively, via comparison of the HPLC retention time and mass spectra with authentic standards. A minor metabolic fate involved oxidation by cytochrome P450 to yield monohydroxylated metabolites M1 and M3 and des-ethyl ertugliflozin (M2), which accounted for ̃5.2% of the dose in excreta. In plasma, unchanged ertugliflozin and the corresponding 4-O-β- (M4a) and 3-O-β (M4c) glucuronides were the principal components, which accounted for 49.9, 12.2, and 24.1% of the circulating radioactivity. Overall, these data suggest that ertugliflozin is well absorbed in humans, and eliminated largely via glucuronidation. © 2013 by The American Society for Pharmacology and Experimental Therapeutics.


Kung D.W.,Worldwide Medicinal Chemistry | Griffith D.A.,Worldwide Medicinal Chemistry | Esler W.P.,Metabolic and Endocrine Diseases Research Unit | Vajdos F.F.,Structural Biology | And 19 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2015

A novel series of spirocyclic-diamine based, isoform non-selective inhibitors of acetyl-CoA carboxylase (ACC) is described. These spirodiamine derivatives were discovered by design of a library to mimic the structural rigidity and hydrogen-bonding pattern observed in the co-crystal structure of spirochromanone inhibitor I. The lead compound 3.5.1 inhibited de novo lipogenesis in rat hepatocytes, with an IC50 of 0.30 μM. © 2015 Elsevier Ltd. All rights reserved.


PubMed | Pfizer, Structural Biology, Primary Pharmacology Group, Metabolic and Endocrine Diseases Research Unit and 2 more.
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2015

A novel series of spirocyclic-diamine based, isoform non-selective inhibitors of acetyl-CoA carboxylase (ACC) is described. These spirodiamine derivatives were discovered by design of a library to mimic the structural rigidity and hydrogen-bonding pattern observed in the co-crystal structure of spirochromanone inhibitor I. The lead compound 3.5.1 inhibited de novo lipogenesis in rat hepatocytes, with an IC50 of 0.30 M.


Straub S.V.,Metabolic and Endocrine Diseases Research Unit | Perez S.M.,Metabolic and Endocrine Diseases Research Unit | Tan B.,Dynamics and Metabolism | Coughlan K.A.,Pfizer | And 5 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2011

Pharmacological inhibition of Kv1.3 fails to modulate insulin sensitivity in diabetic mice or human insulin-sensitive tissues. Am J Physiol Endocrinol Metab 301: E380-E390,+011. First published May 17, 2011; doi:10.1152/ajpendo.00076.2011.-Genetic ablation of the voltagegated potassium channel Kv1.3 improves insulin sensitivity and increases metabolic rate in mice. Inhibition of Kv1.3 in mouse adipose and skeletal muscle is reported to increase glucose uptake through increased GLUT4 translocation. Since Kv1.3 represents a novel target for the treatment of diabetes, the present study investigated whether Kv1.3 is functionally expressed in human adipose and skeletal muscle and whether specific pharmacological inhibition of the channel is capable of modulating insulin sensitivity in diabetic mouse models. Voltage-gated K+ channel currents in human skeletal muscle cells (SkMC) were insensitive to block by the specific Kv1.3 blockers 5-(4-phenoxybutoxy)psoralen (PAP-1) and margatoxin (MgTX). Glucose uptake into SkMC and mouse 3T3-L1 adipocytes was also unaffected by treatment with PAP-1 or MgTX. Kv1.3 protein expression was not observed in human adipose or skeletal muscle from normal and type 2 diabetic donors. To investigate the effect of specific Kv1.3 inhibition on insulin sensitivity in vivo, PAP-1 was administered to hyperglycemic mice either acutely or for 5 days prior to an insulin tolerance test. No effect on insulin sensitivity was observed at free plasma PAP-1 concentrations that are specific for inhibition of Kv1.3. Insulin sensitivity was increased only when plasma concentrations of PAP-1 were sufficient to inhibit other Kv1 channels. Surprisingly, acute inhibition of Kv1.3 in the brain was found to ecrease insulin sensitivity in ob/ob mice. Overall, these findings are not supportive of a role for Kv1.3 in the modulation of peripheral insulin sensitivity. © 2011 the American Physiological Society.

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