Prodrugs of phosphates, phosphonates, and phosphinates

Krise, Jeffrey P.; Stella, Valentino J.

doi:10.1016/0169-409x(95)00111-j

Cited by 167 publications

(83 citation statements)

References 113 publications

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“…The negatively charged phosphonic acid moiety, although useful in this case for achieving high FBPase binding affinity, is often associated with low oral bioavailability and poor cell penetration and consequently is not usually considered a desirable feature. Phosphonate prodrug strategies designed to circumvent the low oral bioavailability rarely provide a satisfactory solution, because most known prodrug classes are plagued by aqueous instability, poor conversion rates, and͞or byproductrelated toxicities (38). In contrast, the bisamidate prodrug described here, MB06322, exhibits good stability across a broad pH range, generates nontoxic byproducts, and results in satisfactory oral bioavailability in the rat (Ͼ20%).…”

Section: Discussionmentioning

confidence: 97%

“…MB05032, like most phosphonic acids, exhibits low oral bioavailability in animals (Ͻ2%) (data not shown). Accordingly, a large set of known phosphonic acid prodrugs (38) and novel prodrugs (39) were prepared and extensively evaluated in an effort to find a prodrug with improved oral bioavailability, good aqueous stability, and no risk of prodrug byproductrelated toxicity. These efforts led to the discovery of a bisamidate prodrug series, which unlike other phosphonate prodrugs, had all of the desired properties.…”

Section: Resultsmentioning

confidence: 99%

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MB06322 (CS-917): A potent and selective inhibitor of fructose 1,6-bisphosphatase for controlling gluconeogenesis in type 2 diabetes

Erion

Poelje

Dang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

144

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In type 2 diabetes, the liver produces excessive amounts of glucose through the gluconeogenesis (GNG) pathway and consequently is partly responsible for the elevated glucose levels characteristic of the disease. In an effort to find safe and efficacious GNG inhibitors, we targeted the AMP binding site of fructose 1,6-bisphosphatase (FBPase). The hydrophilic nature of AMP binding sites and their widespread use for allosteric regulation of enzymes in metabolic pathways has historically made discovery of AMP mimetics suitable for drug development difficult. By using a structure-based drug design strategy, we discovered a series of compounds that mimic AMP but bear little structural resemblance. The lead compound, MB05032, exhibited high potency and specificity for human FBPase. Oral delivery of MB05032 was achieved by using the bisamidate prodrug MB06322 (CS-917), which is converted to MB05032 in two steps through the action of an esterase and a phosphoramidase. MB06322 inhibited glucose production from a variety of GNG substrates in rat hepatocytes and from bicarbonate in male Zucker diabetic fatty rats. Analysis of liver GNG pathway intermediates confirmed FBPase as the site of action. Oral administration of MB06322 to Zucker diabetic fatty rats led to a dose-dependent decrease in plasma glucose levels independent of insulin levels and nutritional status. Glucose lowering occurred without signs of hypoglycemia or significant elevations in plasma lactate or triglyceride levels. The findings suggest that potent and specific FBPase inhibitors represent a drug class with potential to treat type 2 diabetes through inhibition of GNG.endogenous glucose production ͉ AMP mimetic ͉ structure-based drug design ͉ phosphonate prodrug ͉ antihyperglycemic T he liver (1, 2) and, to a lesser extent, the kidneys (3) are the primary organs responsible for endogenous glucose production (EGP). In type 2 diabetes mellitus (T2DM), excessive EGP in the fasted state and fed state contributes to the chronic elevation of blood glucose levels found in patients with advanced (4, 5) and mild diabetes (6, 7). Moreover, fasting plasma glucose levels correlate with EGP rates in patients with fasting plasma glucose Ͼ180 mg͞dl (10 mM) (8) and possibly in patients with lower levels (6, 7). Studies using 13 C NMR spectroscopy (9) as well as more recent studies using deuterated water (7, 10) attribute the excessive EGP in T2DM patients to increased flux through the gluconeogenesis (GNG) pathway.Efforts over the past 40 years to discover inhibitors of GNG produced few safe and effective drug candidates (11). Metformin, the only marketed drug that acts, at least partially, through inhibition of GNG (12), inhibits GNG indirectly and only 33-36% at the rarely prescribed maximal human dose (13). Direct GNG inhibitors show more pronounced glucose lowering in animals but not without eliciting safety-related concerns. Hypoglycemia, lactic acidosis, and hypertriglyceridemia are the principle safety risks associated with GNG inhibition as highlighted in studie...

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Section: Discussionmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

MB06322 (CS-917): A potent and selective inhibitor of fructose 1,6-bisphosphatase for controlling gluconeogenesis in type 2 diabetes

Erion

Poelje

Dang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

144

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“…Phosphate esters are a widely used prodrug strategy for improving the aqueous solubility, not only oral but also and especially drugs intended for parenteral administration (Krise and Stella, 1996;Stella and Nti-Addae, 2007;. The active parent drug molecule is rapidly released from phosphate prodrugs by endogenous phosphatases, such as alkaline phosphatase.…”

Section: A Improving Formulation and Administrationmentioning

confidence: 99%

Prodrugs—from Serendipity to Rational Design

2011

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“…It has been described that short alkyl chain esters of phosphonates are metabolically quite stable. 56,57 Incubation with rat liver microsomes showed that both compounds, 19a and 19c, were relatively stable toward liver enzymes. Only a very small percentage (<5%) was metabolized under the applied conditions (see Experimental Section), while >95% of the compounds were recovered unchanged.…”

Section: Investigation Of Chemical and Metabolic Stabilitymentioning

confidence: 99%

Selective Nucleoside Triphosphate Diphosphohydrolase-2 (NTPDase2) Inhibitors: Nucleotide Mimetics Derived from Uridine-5′-carboxamide

et al. 2008

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Ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases, subtypes 1, 2, 3, 8 of NTPDases) dephosphorylate nucleoside tri-and diphosphates to the corresponding di-and monophosphates. In the present study we synthesized adenine and uracil nucleotide mimetics, in which the phosphate residues were replaced by phosphonic acid esters attached to the nucleoside at the 5′-position by amide linkers. Among the synthesized uridine derivatives, we identified the first potent and selective inhibitors of human NTPDase2. The most potent compound was 19a (PSB-6426), which was a competitive inhibitor of NTPDase2 exhibiting a K i value of 8.2 μM and selectivity versus other NTPDases. It was inactive toward uracil nucleotide-activated P2Y 2 , P2Y 4 , and P2Y 6 receptor subtypes. Compound 19a was chemically and metabolically highly stable. In contrast to the few known (unselective) NTPDase inhibitors, 19a is an uncharged molecule and may be perorally bioavailable. NTPDase2 inhibitors have potential as novel cardioprotective drugs for the treatment of stroke and for cancer therapy.

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Prodrugs of phosphates, phosphonates, and phosphinates

Cited by 167 publications

References 113 publications

MB06322 (CS-917): A potent and selective inhibitor of fructose 1,6-bisphosphatase for controlling gluconeogenesis in type 2 diabetes

MB06322 (CS-917): A potent and selective inhibitor of fructose 1,6-bisphosphatase for controlling gluconeogenesis in type 2 diabetes

Prodrugs—from Serendipity to Rational Design

Selective Nucleoside Triphosphate Diphosphohydrolase-2 (NTPDase2) Inhibitors: Nucleotide Mimetics Derived from Uridine-5′-carboxamide

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