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C5-Alkyl-2-methylurea-Substituted Pyridines as a New Class of Glucokinase Activators.

ABSTRACT: Glucokinase (GK) activators represent a class of type 2 diabetes therapeutics actively pursued due to the central role that GK plays in regulating glucose homeostasis. Herein we report a novel C5-alkyl-2-methylurea-substituted pyridine series of GK activators derived from our previously reported thiazolylamino pyridine series. Our efforts in optimizing potency, enzyme kinetic properties, and metabolic stability led to the identification of compound 26 (AM-9514). This analogue showed a favorable combination of in vitro potency, enzyme kinetic properties, acceptable pharmacokinetic profiles in preclinical species, and robust efficacy in a rodent PD model.

SUBMITTER: Du X

PROVIDER: S-EPMC4265826 | biostudies-other | 2014 Dec

REPOSITORIES: biostudies-other

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C5-Alkyl-2-methylurea-Substituted Pyridines as a New Class of Glucokinase Activators.

Du Xiaohui X Hinklin Ronald J RJ Xiong Yumei Y Dransfield Paul P Park Jaehyeon J Kohn Todd J TJ Pattaropong Vatee V Lai SuJen S Fu Zice Z Jiao Xianyun X Chow David D Jin Lixia L Davda Jasmine J Veniant Murielle M MM Anderson Deborah A DA Baer Brian R BR Bencsik Josef R JR Boyd Steven A SA Chicarelli Mark Joseph MJ Mohr Peter J PJ Wang Bin B Condroski Kevin R KR DeWolf Walter E WE Conn Marion M Tran Thanhvien T Yang Jerry J Aicher Thomas D TD Medina Julio C JC Coward Peter P Houze Jonathan B JB

ACS medicinal chemistry letters 20141122 12

Glucokinase (GK) activators represent a class of type 2 diabetes therapeutics actively pursued due to the central role that GK plays in regulating glucose homeostasis. Herein we report a novel C5-alkyl-2-methylurea-substituted pyridine series of GK activators derived from our previously reported thiazolylamino pyridine series. Our efforts in optimizing potency, enzyme kinetic properties, and metabolic stability led to the identification of compound 26 (AM-9514). This analogue showed a favorable ...[more]

PMID: 25516785

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Project description:The incorporation of C5-amino-modified 2'-deoxyuridine analogues into DNA have found application in nucleic acid labelling, the stabilization of nucleic acid structures, functionalization of nucleic acid aptamers and catalysts, and the investigation of sequence-specific DNA bending. In this study, we describe the physicochemical properties of four different C5-amino-modified 2'-deoxyuridines in which the amino group is tethered to the base via a 3-carbon alkyl, Z- or E-alkenyl or alkynyl linker. Conformational parameters of the nucleosides and their pK(a) values were deduced using 1H NMR. All of them display the expected anti-conformation of the nucleoside with 2'-endo sugar puckers for the deoxyribose ring. A preference for the cisoid conformation for the Z-alkenyl analogue is found, while the E-alkenyl analogue exists exclusively as its transoid conformation. The pK(a) values range from 10.0 for the analogue with an aliphatic propyl linker to 8.5 for the propargylamino analogue. The analogues have been used for the synthesis of triple-helix forming oligonucleotides (TFOs) in which they replace thymidine in the natural sequence. Oligonucleotides containing the propargylamino analogue display the highest stability especially at low pH, while those containing analogues with propyl and especially Z-alkenyl linkers are destabilized to a great extent. TFOs containing the analogue with the E-alkenyl linker have stability similar to the unmodified structures. The chemical synthesis of TFOs containing the analogue, 5-(3-hydroxyprop-1-ynyl)-2'-deoxyuridine that possesses a neutral but polar side chain show a remarkable stability, which is higher than that of all TFOs containing the alkylamino or alkenylamino analogues and only slightly lower than that of TFOs containing the propargylamino analogue. Both the hydroxyl and propargylamino substitutions impart enhanced triple-helix stability relative to the analogous sequences containing C5-propynyl-2'-deoxyuridine. Furthermore, a similar dependence of stability on pH is found between TFOs containing the hydroxypropynyl modifications and those containing the propargylamino side chains. This suggests that the major factor responsible for stabilizing such triple helices is due to the presence of the alkyne with an attached electronegative group.

Dataset Information

C5-Alkyl-2-methylurea-Substituted Pyridines as a New Class of Glucokinase Activators.

Publications

C5-Alkyl-2-methylurea-Substituted Pyridines as a New Class of Glucokinase Activators.

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