Vanadium treatment of type 2 diabetes: A view to the future Katherine H. Thompson a, * , Jay Lichter b , Carl LeBel b , Michael C. Scaife b , John H. McNeill c , Chris Orvig a a Medicinal Inorganic Chemistry Group, Chemistry Department, 2036 Main Mall, University of British Columbia, Vancouver, BC, Canada V6T 1Z1 b Akesis Pharmaceuticals, Inc., 888 Prospect Street, Suite 320, La Jolla, CA 92037, USA c Faculty of Pharmaceutical Sciences, 2146 East Mall, University of British Columbia, Vancouver, BC, Canada V6T 1Z3 article info Article history: Received 24 September 2008 Received in revised form 10 November 2008 Accepted 4 December 2008 Available online 24 December 2008 Keywords: Vanadium Bis(ethylmaltolato)oxovanadium(IV) Diabetes mellitus Biodistribution abstract 3-Hydroxy-2-methyl-4-pyrone and 2-ethyl-3-hydroxy-4-pyrone (maltol and ethyl maltol, respectively) have proven especially suitable as ligands for vanadyl ions, in potential insulin enhancing agents for dia- betes mellitus. Both bis(maltolato)oxovanadium(IV) (BMOV), and the ethylmaltol analog, bis(ethylmalto- lato)oxovanadium(IV) (BEOV), have the desired intermediate stability for pro-drug use, and have undergone extensive pre-clinical testing for safety and efficacy. Pharmacokinetic evaluation indicates a pattern of biodistribution consistent with fairly rapid dissociation and uptake, binding to serum transfer- rin for systemic circulation and transport to tissues, with preferential uptake in bone. These bis-ligand oxovanadium(IV) (VOL 2 ) compounds have a clear advantage over inorganic vanadyl sulfate in terms of bioavailability and pharmaceutical efficacy. BEOV has now completed Phase I and has advanced to Phase II clinical trials. In the Phase I trial, a range of doses from 10 mg to 90 mg BEOV, given orally to non-dia- betic volunteers, resulted in no adverse effects; all biochemical parameters remained within normal lim- its. In the Phase IIa trial, BEOV (AKP-020), 20 mg, daily for 28 days, per os, in seven type 2 diabetic subjects, was associated with reductions in fasting blood glucose and %HbA1c; improved responses to oral glucose tolerance testing, versus the observed worsening of diabetic symptoms in the two placebo controls. Ó 2009 Elsevier Inc. All rights reserved. 1. Introduction Vanadium compounds can be used to mitigate insufficient insu- lin response in diabetes mellitus. They cannot entirely substitute for lack of insulin (as in type 1 diabetes), but they can reduce reli- ance on exogenous insulin, or perhaps substitute for other oral hypoglycemic agents, in type 2 diabetes. To date, the main draw- backs to more widespread use have been gastrointestinal distress and low absorptive efficiency, both of which are amenable to im- proved ligand design [1]. Now, with the completion of the first Phase IIa trial [first reported at the Vanadium 6 Symposium, Lis- bon, Portugal, 18 July, 2008], the future of vanadium compounds for treatment of diabetes looks more promising than ever. Herein we consider what the most recent studies indicate for future ther- apeutic use. 2. Vanadium complexes of maltol and ethyl maltol as insulin enhancing agents Bis(2-ethyl-3-hydroxy-4-pyronato)oxovanadium(IV) (BEOV), was first synthesized in the late 1990s, as one in a series of compounds containing maltolato ligand variants [2]. The ligand, 2-ethyl-3-hydroxy-4-pyrone, also known as ethyl maltol, is very similar to maltol, 3-hydroxy-2-methyl-4-pyrone (Fig. 1), which has been used as a flavoring agent for baked goods and some bev- erages, including beer, for the last half century [3]. Ethyl maltol is also an approved food additive [3]. Both maltol and ethyl maltol form bis(ligand) oxovanadium(IV) complexes that are orally avail- able ‘insulin mimics’ [2,4,5]. Acute and chronic studies of bis(3-hy- droxy-2-methyl-4-pyronato)oxovanadium(IV), BMOV, in STZ- diabetic rats [4], showed improved potency and efficacy of the che- lated compound, as compared to a common inorganic vanadium salt, vanadyl sulfate [6]. Over time, BMOV has become the ‘bench- mark’ compound against which all other vanadium-based hypogly- cemic agents have been compared [2,7]. In vivo response to BEOV as an anti-diabetic agent was virtually the same as that to BMOV, in short-term screening trials, in STZ-diabetic rats [8]. Although the first trials of inorganic vanadium compounds in diabetic patients were carried out in the early 1990s [9–11], some gastrointestinal irritation and inconclusive alterations in plasma glucose levels left some doubt as to the viability of the invention. Doses up to 2 mmol V d À1 , as either vanadyl sulfate or ammonium metavanadate did not consistently improve glycemic control [12]. What was needed was a way to increase the bioavailability such that a lower dose of vanadium could be given, without loss of efficacy. 0162-0134/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jinorgbio.2008.12.003 * Corresponding author. Tel.: +1 604 822 3668; fax: +1 604 822 2391. E-mail address: kthompso@chem.ubc.ca (K.H. Thompson). Journal of Inorganic Biochemistry 103 (2009) 554–558 Contents lists available at ScienceDirect Journal of Inorganic Biochemistry journal homepage: www.elsevier.com/locate/jinorgbio