Discovery of DA-1229: A potent, long acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes

Kim, Heung Jae; Kwak, Woo Young; Min, Jong Pil; Lee, Jae Young; Yoon, Tae Hyun; Kim, Ha Dong; Shin, Chang Yell; Kim, Mi Kyung; Choi, Songa; Kim, Hae Sun; Yang, Eun Kyoung; Cheong, Ye Hwang; Chae, Yu Na; Park, Kyung Jin; Jang, Ji Myun; Choi, Soo Jung; Son, Miwon; Kim, Soon Hoe; Yoo, Moohi; Lee, Bong Jin

doi:10.1016/j.bmcl.2011.04.029

Cited by 50 publications

(30 citation statements)

References 17 publications

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“…Evogliptin (DA-1229) is a piperazine derivative that is in clinical development as a novel DPP-IV inhibitor for the treatment of type 2 DM ( Figure 1 ). 8 – 11 The DPP-IV inhibition of evogliptin was demonstrated to be reversible, highly potent, and selective in in vitro studies. 8 It has the half maximal inhibitory concentration (IC 50 ) value of 0.9 in human plasma for DPP-IV, with a 6,000 times higher potency compared to human DPP-VIII and DPP-IX, as well as with more than 20,000 times greater potency compared to human DPP-I, DPP-II, fibroblast activation protein-alpha (FAPα), antiphagocytic protein 1 (APP1), prolidase, and granzyme B.…”

Section: Introductionmentioning

confidence: 99%

Multiple-dose pharmacokinetics and pharmacodynamics of evogliptin (DA-1229), a novel dipeptidyl peptidase IV inhibitor, in healthy volunteers

Gu¹,

Park²,

Kim³

et al. 2014

DDDT

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PurposeEvogliptin (DA-1229) is a novel, potent, and selective dipeptidyl peptidase IV (DPP-IV) inhibitor in clinical development for the treatment of type 2 diabetes mellitus. This study aimed to investigate the pharmacokinetic and pharmacodynamic profiles and tolerability of evogliptin after repeated oral administration in healthy subjects.Patients and methodsA block-randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation study was performed in a total of 30 subjects. Repeated once-daily doses of 5, 10, or 20 mg evogliptin or the same doses of placebo were orally administered to ten subjects in each dosage group for 10 days. Subjects in each group were randomized to receive evogliptin or placebo with a ratio of 8:2. Pharmacokinetics of evogliptin were evaluated, with its concentrations in serial plasma and urine samples collected following the first and last administrations. DPP-IV activity and glucagon-like peptide-1, glucose, and insulin levels were quantified to evaluate evogliptin’s pharmacodynamics on the first and last dosing days.ResultsAll participants completed the study without any serious or severe adverse event. The evogliptin plasma concentration reached its peak within 4–5 hours and decreased relatively slowly, with a terminal elimination half-life of 33–39 hours. Repeated administration resulted in a 1.4- to 1.5-fold accumulation. Evogliptin’s systemic exposure and inhibition of plasma DPP-IV activity increased in a dose-dependent manner. Inhibition of DPP-IV activity >80% was sustained over 24 hours in all evogliptin dose groups and provided an increase in postprandial active glucagon-like peptide-1 levels by 1.5- to 2.4-fold. Postprandial glucose levels in the evogliptin-treated groups were reduced 20%–35% compared to placebo, but were not accompanied by increased insulin levels.ConclusionRepeated administration of evogliptin in healthy subjects was well tolerated and exhibited linear pharmacokinetics within the 5–20 mg dose range. A once-daily regimen of 5–20 mg evogliptin effectively inhibited DPP-IV activity.

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Section: Introductionmentioning

confidence: 99%

Multiple-dose pharmacokinetics and pharmacodynamics of evogliptin (DA-1229), a novel dipeptidyl peptidase IV inhibitor, in healthy volunteers

Gu¹,

Park²,

Kim³

et al. 2014

DDDT

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“…This molecule is a reversible and competitive inhibitor of DPPIV, with an inhibitory activity almost 6000-fold more selective for human DPP4 compared with human DPP8 or DPP9. 25 In streptozotocin-induced diabetic mice, DA-1229 has been shown to significantly reduce plasma DPPIV activity, enhance glucagon-like peptide-1 levels and improve insulin tolerance. 26 In high-fat diet-induced obese mice, long-term treatment with DA-1229 resulted in significantly improved glucose intolerance and insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

DA-1229, a dipeptidyl peptidase IV inhibitor, protects against renal injury by preventing podocyte damage in an animal model of progressive renal injury

Lee

Kim

et al. 2016

Laboratory Investigation

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“…Series A began with the preparation of the 4-(substituted)-3oxo-piperazine-1-carboxylic acid tert-butyl esters (3) according to the literature procedure 13 by addition of the substituted benzyl chlorides (1) to a solution of 1-Boc-3-oxopiperazine (2) in anhydrous DMF in the presence of NaH (Scheme 1). Deprotection of the Boc protecting group of (3) was achieved using 4 M HCl Fig.…”

Section: Chemistrymentioning

confidence: 99%

“…4.2.1.1. tert-Butyl 4-(4-fluorobenzyl)-3-oxopiperazine-1-carboxylate (3a) 13 . Synthesised using 1-chloromethyl-4-fluorobenzene (0.43 g, 2.9 mmol).…”

Section: General Experimentalmentioning

confidence: 99%

“…4-(3-(1H-imidazol-1-yl)propyl)-1-(4-fluorobenzyl)piperazin-2-one (6a). Synthesised according to the general procedure using 5a (0.15 g, 0.45 mmol) Yield: 48% as a yellow oil.1 H NMR (CDCl 3 ): d 7.47 (s, 1H, imidazole), 7.24 (m, 2H, Ar), 7.06 (s, 1H, imidazole), 7.02 (m, 2H, Ar), 6.90 (s, 1H, imidazole), 4.5 (s, 2H,CH 2 ), 4.04 (t, J = 6.7 Hz, 2H, CH 2 ), 3.23 (t, J = 5.4 Hz, 2H, CH 2 ), 3.19 (s, 2H, CH 2 ), 2.61 (t, J = 5.4 Hz, 2H, CH 2 ), 2.34 (t, J = 6.6 Hz, 2H, CH 2 ), 1.94 (m, 2H, CH 2 ) 13. C NMR (CDCl 3 ): d 166.7 (C@O), 163.3 (C-F), 161.3 (C-F), 137.3 (CH, imidazole), 132.3 (C), 129.9 (2 Â CH-Ar), 129.5 (CH, imidazole), 118.8 (CH, imidazole), 115.5 (2 Â CH, Ar), 57.1 (CH 2 ), 53.6 (CH 2 ), 50.0 (CH 2 ), 48.8 (CH 2 ), 45.8 (CH 2 ), 44.2 (CH 2 ), 27.9 (CH 2 ).…”

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confidence: 99%

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Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics

El-wahab

Accietto

Mariño

et al. 2018

Bioorganic & Medicinal Chemistry

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Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH-imidazole or CH-triazole moiety to enhance binding interaction with the heme of CYP121A1. The series displayed moderate to weak type II binding affinity for CYP121A1, with the exception of series B 10a, which displayed mixed type I binding. Of the three series, series C imidazole derivatives showed the best, although modest, inhibitory activity against M. tuberculosis (17d MIC = 12.5 μg/mL, 17a 50 μg/mL). Crystal structures were determined for CYP121A1 bound to series A compounds 6a and 6b that show the imidazole groups positioned directly above the haem iron with binding between the haem iron and imidazole nitrogen of both compounds at a distance of 2.2 Å. A model generated from a 1.5 Å crystal structure of CYP121A1 in complex with compound 10a showed different binding modes in agreement with the heterogeneous binding observed. Although the crystal structures of 6a and 6b would indicate binding with CYP121A1, the binding assays themselves did not allow confirmation of CYP121A1 as the target.

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Discovery of DA-1229: A potent, long acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes

Cited by 50 publications

References 17 publications

Multiple-dose pharmacokinetics and pharmacodynamics of evogliptin (DA-1229), a novel dipeptidyl peptidase IV inhibitor, in healthy volunteers

Multiple-dose pharmacokinetics and pharmacodynamics of evogliptin (DA-1229), a novel dipeptidyl peptidase IV inhibitor, in healthy volunteers

DA-1229, a dipeptidyl peptidase IV inhibitor, protects against renal injury by preventing podocyte damage in an animal model of progressive renal injury

Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics

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