(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

Biftu, Tesfaye; Feng, Danqing; Qian, Xiaoxia; Liang, Gui-Bai; KIECZYKOWSKI, G. R.; Eiermann, George J.; He, Huaibing; Leiting, Barbara; Lyons, Kathy; Petrov, A. N.; SinhaRoy, Ranabir; Zhang, Bei; Scapin, Giovanna; Patel, S. K.; Gao, Ying‐Duo; Singh, Suresh B.; Wu, Joseph K.; Zhang, Xiaoping; Thornberry, Nancy A.; Weber, Ann E.

doi:10.1016/j.bmcl.2006.09.099

Cited by 44 publications

(28 citation statements)

References 23 publications

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“…All the series of DPP‐IV inhibitors analyzed in the present review fulfill the following criteria: (a) they contain compounds with bioactivity in humans in the nM range, (b) they also contain compounds that are at least tenfold less potent in humans than the most active compounds in their corresponding series, and (c) at least one compound of the series (or a very similar one from elsewhere) has been crystallized in a complex with human DPP‐IV. This last point is crucial because correctly predicting the binding mode of all the compounds in a series is necessary in order to offer valid explanations for the activity and selectivity cliffs relative to the protein environment.…”

Section: Selecting the Dpp‐iv Inhibitor Series That Give Clues On Howmentioning

confidence: 99%

“…Therefore, in order to observe the importance for bioactivity of these intermolecular interactions with Glu205, Glu206, and Tyr662, we have compared different pairs of DPP‐IV inhibitors whose structure differs only in the region facing these residues, focusing on how their bioactivities are affected by (a) their different capacity to form salt bridges/hydrogen bonds with the N‐terminal recognition region, and (b) the electrostatic surfaces they create in this area. We have observed activity cliffs subjected to changes of this NH 3 + group in different situations: (a) when the configuration of the carbon containing the NH 3 + group is switched from R to S (see Figure A and Supporting Information Figure B and E ); (b) when the NH 3 + group is replaced by a hydrogen atom and a charged secondary amine is introduced in the adjacent carbon (see Figure and Supporting Information Figure A and C–F); (c) when the relative location of the amino substituent in the compound makes its protonation more difficult (see Figure C); and (d) when the positive NH 3 + group is replaced by an alcohol group that is also capable of making hydrogen bonds with Glu205, Glu206, and Tyr662 but not of producing the electrostatic interaction with the Glu205/Glu206 dyad (see Figure D) …”

Section: How To Favor Potent and Selective Dpp‐iv Inhibitors Accordinmentioning

confidence: 99%

“…Comparison of the distribution of electrostatic surfaces between pairs of compounds that differ in their interactions with residues Glu205, Glu206, and Tyr662 Notes : For each panel the compound with the highest activity is shown in purple on the left and the compound with the lowest activity is shown in green on the right. Molecules are labeled with the same names that identify them in the corresponding paper . The negative and positive electrostatic surface differences are shown in garnet and blue respectively (where the default value, i.e., 2.0 was used as the threshold for the surface difference between each pair).…”

Section: How To Favor Potent and Selective Dpp‐iv Inhibitors Accordinmentioning

confidence: 99%

“…In the 2D representation of each ligand, the structural differences between the compounds compared are highlighted. The different panels are arranged in order of decreasing disparity and correspond to different situations: in panel A , the configuration of the carbon containing the NH 3 + group is switched from (R) in 18 to (S) in 21 ; in panel B , the NH 3 + group is replaced by H and a positively charged secondary amine is introduced into the adjacent carbon; in panel C , the substituent containing the amine group is shortened and the resulting amine is more difficult to protonate at pH = 7; and in panel D , the positive NH 3 + group is replaced by an alcohol group . The ligand orientations are the result of their superposition with co‐crystallized ligands from the same or very similar chemical series (i.e., 2IIV for panel A , 4A5S for panel B, and 3OPM for panels C and D ; residue locations in each panel are also taken from the corresponding PDB file).…”

Section: How To Favor Potent and Selective Dpp‐iv Inhibitors Accordinmentioning

confidence: 99%

“…It has been described that Arg125 is essential to coordinate the carbonyl group of the P 2 residue and, together with Glu205 and Glu206, align the substrate optimally for the nucleophilic attack by Ser630 . Moreover, SAR studies suggest that an electrostatic intermolecular interaction with the positively charged Arg125 results in an affinity gain for DPP‐IV . In this regard, an optimal protein‐ligand fit might be reached by an inhibitor moiety that introduces a negative (or less positive) environment close to Arg125.…”

Section: How To Favor Potent and Selective Dpp‐iv Inhibitors Accordinmentioning

confidence: 99%

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Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

Ojeda-Montes

Gimeno

Tomás-Hernández

et al. 2018

Medicinal Research Reviews

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The inhibition of dipeptidyl peptidase-IV (DPP-IV) has emerged over the last decade as one of the most effective treatments for type 2 diabetes mellitus, and consequently (a) 11 DPP-IV inhibitors have been on the market since 2006 (three in 2015), and (b) 74 noncovalent complexes involving human DPP-IV and drug-like inhibitors are available at the Protein Data Bank (PDB). The present review aims to (a) explain the most important activity cliffs for DPP-IV noncovalent inhibition according to the binding site structure of DPP-IV, (b) explain the most important selectivity cliffs for DPP-IV noncovalent inhibition in comparison with other related enzymes (i.e., DPP8 and DPP9), and (c) use the information deriving from this activity/selectivity cliff analysis to suggest how virtual screening protocols might be improved to favor the early identification of potent and selective DPP-IV inhibitors in molecular databases (because they have not succeeded in identifying selective DPP-IV inhibitors with IC ≤ 100 nM). All these goals are achieved with the help of available homology models for DPP8 and DPP9 and an analysis of the structure-activity studies used to develop the noncovalent inhibitors that form part of some of the complexes with human DPP-IV available at the PDB.

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Section: Selecting the Dpp‐iv Inhibitor Series That Give Clues On Howmentioning

confidence: 99%

Section: How To Favor Potent and Selective Dpp‐iv Inhibitors Accordinmentioning

confidence: 99%

Section: How To Favor Potent and Selective Dpp‐iv Inhibitors Accordinmentioning

confidence: 99%

Section: How To Favor Potent and Selective Dpp‐iv Inhibitors Accordinmentioning

confidence: 99%

Section: How To Favor Potent and Selective Dpp‐iv Inhibitors Accordinmentioning

confidence: 99%

See 3 more Smart Citations

Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

Ojeda-Montes

Gimeno

Tomás-Hernández

et al. 2018

Medicinal Research Reviews

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Dipeptidyl Peptidase 4 Inhibitors

Weber

Thornberry

2010

Burger's Medicinal Chemistry and Drug Discovery

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Defective insulin secretion is a hallmark of type 2 diabetes (T2DM), and agents that increase the concentration of circulating insulin have proven beneficial in the treatment of diabetes. Dipeptidyl peptidase 4 (DPP‐4) inhibitors are a new oral approach to T2DM that lower glucose via stabilization of the incretin hormone glucagon‐like peptide 1 (GLP‐1), which has clearly established roles in insulin secretion and inhibition of glucagon production. These agents have been shown to produce clinically meaningful glucose control in a range of patients with type 2 diabetes without many of the liabilities that are associated with other oral therapies, including weight gain, edema, GI intolerability, and hypoglycemia. Accordingly, DPP‐4 inhibitors have excellent potential for use in both monotherapy and combination with established agents. Extensive structure–activity relationship (SAR) studies in many different laboratories have resulted in the identification of a number of clinical candidates. The most advanced of these have recently been approved for the treatment of T2DM, representing the first new oral therapy for treatment of this disease since the introduction of troglitazone in 1998.

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Dipeptidyl Peptidase 4 Inhibitors

Weber¹,

Thornberry²

2021

Burger's Medicinal Chemistry and Drug Discovery

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Type 2 diabetes (T2DM) is a growing worldwide epidemic. While a number of oral agents have been available to treat T2DM, they suffer from safety and tolerability issues and lack durability. In the 1990s, glucagon‐like peptide 1 (GLP‐1) emerged as a new approach to glucose lowering. Endogenous GLP‐1 is rapidly inactivated through the action of dipeptidyl peptidase 4 (DPP‐4), a serine dipeptidyl aminopeptidase that cleaves its N‐terminal two amino acids. Blocking DPP‐4 with a small molecule inhibitor was shown to increase circulating levels of GLP‐1 in rodent models and humans, leading to improved glucose control. Early DPP‐4 inhibitors were dipeptide mimetics, some of which bound to the DPP‐4 active site serine in a covalent manner. Screening and structure‐based drug design led to the identification of many other structural classes. In 2006, sitagliptin became the first DPP‐4 inhibitor approved by the FDA. Inhibitors now available include two for once‐weekly administration. Over 10 years of clinical experience has shown DPP‐4 inhibition to be safe and effective with a low risk of hypoglycemia, no weight gain, and no increased cardiovascular risk. Used as monotherapy or in combination with other glucose‐lowering medications, DPP‐4 inhibitors have become an important class of oral agents to treat T2DM.

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(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

Cited by 44 publications

References 23 publications

Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

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