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.
Subject(s)
Alanine/analogs & derivatives , Amides/chemical synthesis , Diabetes Mellitus, Experimental/drug therapy , Fructose-Bisphosphatase/antagonists & inhibitors , Hypoglycemic Agents/chemical synthesis , Organophosphonates/chemical synthesis , Prodrugs/chemical synthesis , Thiazoles/chemical synthesis , Administration, Oral , Alanine/chemical synthesis , Alanine/pharmacokinetics , Alanine/pharmacology , Amides/pharmacokinetics , Amides/pharmacology , Animals , Biological Availability , Blood Proteins/metabolism , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Male , Mice , Organophosphonates/pharmacokinetics , Organophosphonates/pharmacology , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Protein Binding , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/pharmacologyABSTRACT
Efforts to enhance the inhibitory potency of the initial purine series of fructose-1,6-bisphosphatase (FBPase) inhibitors led to the discovery of a series of benzimidazole analogues with human FBPase IC(50)s < 100 nM. Inhibitor 4.4 emerged as a lead compound based on its potent inhibition of human liver FBPase (IC(50) = 55 nM) and significant glucose lowering in normal fasted rats. Intravenous administration of 4.4 to Zucker diabetic fatty rats led to rapid and robust glucose lowering, thereby providing the first evidence that FBPase inhibitors could improve glycemia in animal models of type 2 diabetes.
Subject(s)
Adenosine Monophosphate/chemistry , Benzimidazoles/pharmacology , Drug Design , Enzyme Inhibitors/pharmacology , Fructose-Bisphosphatase/antagonists & inhibitors , Organophosphonates/chemistry , Adenosine Monophosphate/metabolism , Animals , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Diabetes Mellitus, Type 2/drug therapy , Disease Models, Animal , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Liver/enzymology , Molecular Structure , Rats , Rats, Zucker , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Adefovir dipivoxil, a marketed drug for the treatment of hepatitis B, is dosed at submaximally efficacious doses because of renal toxicity. In an effort to improve the therapeutic index of adefovir, 1-aryl-1,3-propanyl prodrugs were synthesized with the rationale that this selectively liver-activated prodrug class would enhance liver levels of the active metabolite adefovir diphosphate (ADV-DP) and/or decrease kidney exposure. The lead prodrug (14, MB06866, pradefovir), identified from a variety of in vitro and in vivo assays, exhibited good oral bioavailability (F = 42%, mesylate salt, rat) and rate of prodrug conversion to ADV-DP. Tissue distribution studies in the rat using radiolabeled materials showed that cyclic 1-aryl-1,3-propanyl prodrugs enhance the delivery of adefovir and its metabolites to the liver, with pradefovir exhibiting a 12-fold improvement in the liver/kidney ratio over adefovir dipivoxil.
Subject(s)
Adenine/analogs & derivatives , Liver/metabolism , Organophosphonates/chemical synthesis , Organophosphorus Compounds/chemical synthesis , Adenine/administration & dosage , Adenine/chemical synthesis , Adenine/pharmacokinetics , Administration, Oral , Animals , Biological Availability , Dogs , Hepatocytes/metabolism , In Vitro Techniques , Male , Microsomes, Liver/metabolism , Organophosphonates/administration & dosage , Organophosphonates/pharmacokinetics , Organophosphorus Compounds/administration & dosage , Organophosphorus Compounds/pharmacokinetics , Prodrugs , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Tissue DistributionABSTRACT
Chronic inflammatory diseases, such as arthritis and rheumatoid arthritis, remain major health problems worldwide. We previously demonstrated that adenosine kinase inhibitors (AKIs) exhibit antiinflammatory effects by inhibiting TNF-alpha production, neutrophil accumulation, and edema formation. Although adenosine receptor agonists produce similar effects, AKIs showed the antiinflammatory activity without the cardiovascular side effects that prevented the development of adenosine receptor specific agonists. However, previously described potent AKIs, such as 5-iodotubercidin, are nucleosides which have the potential to undergo in vivo 5'-O-phosphorylation and therefore produce cytotoxicity. In an effort to eliminate toxicities produced by phosphorylated nucleosides, l-lyxofuranosyl analogues of tubercidin were tested as potential AKIs since the opposite stereochemical orientation of the CH(2)OH was expected to eliminate intracellular phosphorylation. Described herein are the discovery of a new series of AKIs based on alpha-l-lyxofuranosyl nucleosides, their SAR, as well as the antiinflammatory activity of the lead compound GP790 (IC(50) = 0.47 nM, 47% inhibition of paw swelling at 10 mg/kg in rat carrageenan paw edema model). In addition, a study showing that in the skin lesion model the antiinflammatory activity is reversed by an A2 selective adenosine receptor antagonist 3,7-dimethyl-1-propargyl xanthine [correction of propylxanthine] (DMPX) is also described.