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
| Autor: | Jay DaRe, Tao Jiang, Scott C. Potter, Tony Gibson, Qun Dang, Frank Taplin, Yan Liu, Mark D. Erion, Daniel K. Cashion, Haiqing Li, Zhili Sun, Jason D. Jacintho, Paul D. van Poelje, Srinivas Rao Kasibhatla, Yi Fan, Lemus Robert Huerta, Feng Tian, Wenyu Li |
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| Rok vydání: | 2010 |
| Předmět: |
Purine
Male Benzimidazole Fructose 1 6-bisphosphatase Organophosphonates Administration Oral Biological Availability Pharmacology Diabetes Mellitus Experimental Rats Sprague-Dawley chemistry.chemical_compound Mice Structure-Activity Relationship Drug Discovery Structure–activity relationship Animals Humans Hypoglycemic Agents Prodrugs Thiazole Alanine biology Blood Proteins Prodrug Phosphonate Amides Fructose-Bisphosphatase Rats Thiazoles chemistry Biochemistry Diabetes Mellitus Type 2 biology.protein Molecular Medicine Lead compound Protein Binding |
| Zdroj: | Journal of medicinal chemistry. 54(1) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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