Abstract
Oral delivery of previously disclosed purine and benzimidazole fructose-1,6-bisphosphatase (FBPase) inhibitors via prodrugs failed, which was likely due to their high molecular weight (>600). Therefore, a smaller scaffold was desired, and a series of phosphonic acid-containing thiazoles, which exhibited high potency against human liver FBPase (IC(50) of 10-30 nM) and high selectivity relative to other 5'-adenosinemonophosphate (AMP)-binding enzymes, were discovered using a structure-guided drug design approach. The initial lead compound (30j) produced profound glucose lowering in rodent models of type 2 diabetes mellitus (T2DM) after parenteral administration. Various phosphonate prodrugs were explored without success, until a novel phosphonic diamide prodrug approach was implemented, which delivered compound 30j with good oral bioavailability (OBAV) (22-47%). Extensive lead optimization of both the thiazole FBPase inhibitors and their prodrugs culminated in the discovery of compound 35n (MB06322) as the first oral FBPase inhibitor advancing to human clinical trials as a potential treatment for T2DM.
MeSH terms
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Administration, Oral
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Alanine / analogs & derivatives*
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Alanine / chemical synthesis
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Alanine / pharmacokinetics
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Alanine / pharmacology
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Amides / chemical synthesis*
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Amides / pharmacokinetics
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Amides / pharmacology
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Animals
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Biological Availability
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Blood Proteins / metabolism
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Diabetes Mellitus, Experimental / blood
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Diabetes Mellitus, Experimental / drug therapy*
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Diabetes Mellitus, Type 2 / blood
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Diabetes Mellitus, Type 2 / drug therapy
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Fructose-Bisphosphatase / antagonists & inhibitors*
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Humans
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / pharmacokinetics
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Hypoglycemic Agents / pharmacology
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Male
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Mice
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Organophosphonates / chemical synthesis*
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Organophosphonates / pharmacokinetics
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Organophosphonates / pharmacology
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Prodrugs / chemical synthesis*
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Prodrugs / pharmacokinetics
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Prodrugs / pharmacology
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Protein Binding
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Thiazoles / chemical synthesis*
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Thiazoles / pharmacokinetics
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Thiazoles / pharmacology
Substances
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Amides
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Blood Proteins
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Hypoglycemic Agents
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Organophosphonates
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Prodrugs
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Thiazoles
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N,N'-((5-(2-amino-5-(2-methylpropyl)-4-thiazolyl)-2-furanyl)phosphinylidene)bis(alanine) diethyl ester
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Fructose-Bisphosphatase
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Alanine