Discovery of 2-[4-{{2-(2<i>S</i>,5<i>R</i>)-2-Cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic Acid (ABT-279):  A Very Potent, Selective, Effective, and Well-Tolerated Inhibitor of Dipeptidyl Peptidase-IV, Useful for the Treatment of Diabetes

Madar, David J.; Kopecka, Hana; Pireh, Daisy; Yong, Hong; Pei, Zhonghua; Li, Xiaofeng; Wiedeman, Paul E.; Djurić, Stevan W.; Geldern, Thomas W von; Fickes, Michael G.; Bhagavatula, Lakshmi; McDermott, Todd S.; Wittenberger, Steven J.; Richards, Steven; Longenecker, K.L.; Stewart, Kent D.; Lübben, Thomas; Ballaron, Stephen J.; Stashko, Michael A.; Long, Michelle A.; Wells, Heidi; Zinker, Bradley A.; Mika, Amanda K.; Beno, David W. A.; Kempf-Grote, Anita J; Polakowski, James S.; Segreti, Jason A.; Reinhart, Glenn A.; Fryer, Ryan M.; Sham, Hing L.; Trevillyan, James M.

doi:10.1021/jm060777o

Cited by 38 publications

(16 citation statements)

References 23 publications

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“…In this case, the Ser630 Oγ atom was naturally oriented toward the inhibitor and very close to the inhibitor nitrile C atom (<3 Å, the Oγ atom is colored cyan in Fig. 4e ) (PDB ID: 2AJL [ 42 ], 2G5P, 2G5T, 2G63 [ 33 ], 2I03 [ 43 ], 3BJM (saxagliptin) [ 20 ] and 3W2T (vildagliptin) [ 13 ]). However, for inhibitors that do not require a covalent bond, the Ser630 Oγ atom seems to be oriented in a disorderly manner.…”

Section: Resultsmentioning

confidence: 99%

Comprehensive analysis of the Co-structures of dipeptidyl peptidase IV and its inhibitor

et al. 2016

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BackgroundWe comprehensively analyzed X-ray cocrystal structures of dipeptidyl peptidase IV (DPP-4) and its inhibitor to clarify whether DPP-4 alters its general or partial structure according to the inhibitor used and whether DPP-4 has a common rule for inhibitor binding.ResultsAll the main and side chains in the inhibitor binding area were minimally altered, except for a few side chains, despite binding to inhibitors of various shapes. Some residues (Arg125, Glu205, Glu206, Tyr662 and Asn710) in the area had binding modes to fix a specific atom of inhibitor to a particular spatial position in DPP-4. We found two specific water molecules that were common to 92 DPP-4 structures. The two water molecules were close to many inhibitors, and seemed to play two roles: maintaining the orientation of the Glu205 and Glu206 side chains through a network via the water molecules, and arranging the inhibitor appropriately at the S2 subsite.ConclusionsOur study based on high-quality resources may provide a necessary minimum consensus to help in the discovery of a novel DPP-4 inhibitor that is commercially useful.Electronic supplementary materialThe online version of this article (doi:10.1186/s12900-016-0062-8) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Comprehensive analysis of the Co-structures of dipeptidyl peptidase IV and its inhibitor

et al. 2016

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“…In their development of DPP-IV inhibitors, Abbott also studied adamantane derivatives like 358 (K i = 62 nM, Scheme 52). 672 Focus of this research was on the modification of the cyanopyrrolidin motif, thereby enhancing selectivity for DPP-IV inhibiton over other enzymes. However, their candidate for clinical development is piperidine derivative 359 (ABT-279).…”

Section: Miscellaneous Non-cns Targetsmentioning

confidence: 99%

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

Wanka¹,

Iqbal²,

Schreiner³

2013

Chem. Rev.

579

475

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“…This approach and other structural modifications, for example, vinyl substitution, resulted in the identification of several lead compounds for further preclinical and clinical evaluation, including vildagliptin (LAF‐237) [37,47], sitagliptin (MK‐0431) [46] and saxagliptin (BMS‐477118) [48,49] (table 1). Numerous other molecules with DPP‐IV inhibitory activity have been synthesized and characterized in vitro [50–52].…”

Section: Synthesis and Early Characterization Of Dpp‐iv Inhibitorsmentioning

confidence: 99%

Dipeptidyl peptidase‐IV inhibitors: a major new class of oral antidiabetic drug

Idris¹,

Donnelly²

2007

Diabetes Obesity Metabolism

105

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Exploiting the incretin effect to develop new glucose-lowering treatments has become the focus of intense research. One successful approach has been the development of oral inhibitors of dipeptidyl peptidase-IV (DPP-IV). These drugs reversibly block DPP-IV-mediated inactivation of incretin hormones, for example, glucagon-like peptide 1 (GLP-1) and also other peptides that have alanine or proline as the penultimate N-terminal amino acid. DPP-IV inhibitors, therefore, increase circulating levels and prolong the biological activity of endogenous GLP-1, but whether this is sufficient to fully explain the substantial reduction in haemoglobin A(1c) (HbA(1c)) and associated metabolic profile remains open to further investigation. DPP-IV inhibitors such as vildagliptin and sitagliptin have been shown to be highly effective antihyperglycaemic agents that augment insulin secretion and reduce glucagon secretion via glucose-dependent mechanisms. This review summarizes the major clinical trials with DPP-IV inhibitors as monotherapy and as add-on therapy in patients with type 2 diabetes. The magnitude of HbA(1c) reduction with DPP-IV inhibitors depends upon the pretreatment HbA(1c) values, but there seems to be no change in body weight, and very low rates of hypoglycaemia and gastrointestinal disturbance with these agents. DPP-IV inhibitors represent a major new class of oral antidiabetic drug and their metabolic profile offers a number of unique clinical advantages for the management of type 2 diabetes.

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Discovery of 2-[4-{{2-(2S,5R)-2-Cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic Acid (ABT-279): A Very Potent, Selective, Effective, and Well-Tolerated Inhibitor of Dipeptidyl Peptidase-IV, Useful for the Treatment of Diabetes

Cited by 38 publications

References 23 publications

Comprehensive analysis of the Co-structures of dipeptidyl peptidase IV and its inhibitor

Comprehensive analysis of the Co-structures of dipeptidyl peptidase IV and its inhibitor

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

Dipeptidyl peptidase‐IV inhibitors: a major new class of oral antidiabetic drug

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