mb-05032 and Diabetes-Mellitus--Type-2

mb-05032 has been researched along with Diabetes-Mellitus--Type-2* in 2 studies

Other Studies

2 other study(ies) available for mb-05032 and Diabetes-Mellitus--Type-2

Article	Year
Discovery of a series of phosphonic acid-containing thiazoles and orally bioavailable diamide prodrugs that lower glucose in diabetic animals through inhibition of fructose-1,6-bisphosphatase. Journal of medicinal chemistry, 2011, Jan-13, Volume: 54, Issue:1 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. Topics: Administration, Oral; Alanine; Amides; Animals; Biological Availability; Blood Proteins; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fructose-Bisphosphatase; Humans; Hypoglycemic Agents; Male; Mice; Organophosphonates; Prodrugs; Protein Binding; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thiazoles	2011
Fructose-1,6-bisphosphatase Inhibitors. 2. Design, synthesis, and structure-activity relationship of a series of phosphonic acid containing benzimidazoles that function as 5'-adenosinemonophosphate (AMP) mimics. Journal of medicinal chemistry, 2010, Jan-14, Volume: 53, Issue:1 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. Topics: Adenosine Monophosphate; Animals; Benzimidazoles; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Design; Enzyme Inhibitors; Fructose-Bisphosphatase; Humans; Liver; Molecular Structure; Organophosphonates; Rats; Rats, Zucker; Stereoisomerism; Structure-Activity Relationship	2010

Article

Year

Discovery of a series of phosphonic acid-containing thiazoles and orally bioavailable diamide prodrugs that lower glucose in diabetic animals through inhibition of fructose-1,6-bisphosphatase.

Journal of medicinal chemistry, 2011, Jan-13, Volume: 54, Issue:1

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.

Topics: Administration, Oral; Alanine; Amides; Animals; Biological Availability; Blood Proteins; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fructose-Bisphosphatase; Humans; Hypoglycemic Agents; Male; Mice; Organophosphonates; Prodrugs; Protein Binding; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thiazoles

2011

Fructose-1,6-bisphosphatase Inhibitors. 2. Design, synthesis, and structure-activity relationship of a series of phosphonic acid containing benzimidazoles that function as 5'-adenosinemonophosphate (AMP) mimics.

Journal of medicinal chemistry, 2010, Jan-14, Volume: 53, Issue:1

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.

Topics: Adenosine Monophosphate; Animals; Benzimidazoles; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Design; Enzyme Inhibitors; Fructose-Bisphosphatase; Humans; Liver; Molecular Structure; Organophosphonates; Rats; Rats, Zucker; Stereoisomerism; Structure-Activity Relationship

2010