96999-24-5Relevant articles and documents
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
Dang, Qun,Liu, Yan,Cashion, Daniel K.,Kasibhatla, Srinivas Rao,Jiang, Tao,Taplin, Frank,Jacintho, Jason D.,Li, Haiqing,Sun, Zhili,Fan, Yi,Dare, Jay,Tian, Feng,Li, Wenyu,Gibson, Tony,Lemus, Robert,Van Poelje, Paul D.,Potter, Scott C.,Erion, Mark D.
supporting information; experimental part, p. 153 - 165 (2011/03/19)
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 (IC50 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.
N-(Triisopropylsilyl)pyrrole. A Progenitor "Par Excellence" of 3-Substituted Pyrroles
Bray, Brian L.,Mathies, Peter H.,Naef, Reto,Solas, Dennis R.,Tidwell, Thomas T.,et al.
, p. 6317 - 6328 (2007/10/02)
A very effective strategy has been devised for the synthesis of 3-substituted pyrroles based on the use of the triisopropylsilyl (TIPS) moiety as a sterically demanding nitrogen substituent to obstruct the attack of electrophilic reagents at the α positions. 1-(Triisopropylsilyl)pyrrole (1) undergoes highly preferential kinetic electrophilic substitution at the β position with a variety of electrophiles (Br+, I+, NO2+, RCO+, etc.) and fluoride ion induced desilylation of the products provides the corresponding 3-substituted pyrroles in good overall yields.Competitive trifluoroacetylation experiments demonstrate that substitution of TIPS-pyrrole at the α positions is decelerated by a factor of >104, vs pyrrole at the same sites, without affecting reactivity at the β positions. 1-(Triisopropylsilyl)-3-bromopyrrole (2) is readily converted into the 3-lithio compound 44 by bromine-lithium interchange with alkyllithium reagents.This previously unavailable, formal equivalent of 3-lithiopyrrole is itself an excellent source of a wide range of β-substituted pyrroles, many of which would not be directly preparable from 1.TIPS-pyrrole can be 3,4-dihalogenated and these compounds undergo sequential halogen-metal interchange trapping reactions.This process is exemplified by an efficient, three-step synthesis of the antibiotic verrucarin E (63) from the dibromo compound (5).
FRIEDEL-CRAFTS ACYLATION OF 1-TERT-BUTYLDIMETHYLSILYLPYRROLE, A VERY SHORT AND SIMPLE ROUTE TO 3-SUBSTITUTED PYRROLES.
Simchen, Gerhard,Majchrzak, Michal W.
, p. 5035 - 5036 (2007/10/02)
1-tert-Butyldimethylsilylpyrrole undergoes Friedel-Crafts acylation almost exclusively at β-position giving after sodium fluoride supported hydrolysis the 3-pyrroloketones.
