(3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: A potent, selective, orally active dipeptidyl peptidase IV inhibitor

Ammirati, Mark; Andrews, Kim; Boyer, David A.; Brodeur, Anne M.; Danley, Dennis E.; Doran, Shawn D.; Hulin, Bernard; Liu, Shenping; McPherson, R. Kirk; Orena, Stephen; Parker, Janice C.; Polívková, Jana; Qiu, Xiayang; Soglia, Carolyn B.; Treadway, Judith L.; Vanvolkenburg, Maria A.; Wilder, Donald C; Piotrowski, David W.

doi:10.1016/j.bmcl.2009.02.041

Cited by 37 publications

(24 citation statements)

References 22 publications

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“…In the present study, approximately 29.1% of PF-734200 in the body after a single-dose administration was dialysed by 4-h dialysis, with CLD ranging from 99 to 132 ml min -1 through a 1.8-m 2 dialyser membrane. This degree of elimination is consistent with the low molecular weight, low plasma protein binding and high solubility/permeability of PF-734200 [1]. Moreover, as it is removed by HD to a modest extent, PF-734200 can be administered regardless of the timing of HD in patients with ESRD.…”

Section: Figuresupporting

confidence: 72%

“…PF‐734200 (3,3‐difluoro‐pyrrolidin‐1‐yl)‐[(2S,4S)‐(4‐(4‐pyrimidin‐2‐yl‐piperazin‐1‐yl)‐pyrrolidin‐2‐yl]‐methanone is a potent and selective inhibitor of dipeptidyl peptidase‐IV (DPP‐IV), which, when administered orally, improved glucose tolerance as assessed by a reduction in the maximal glucose excursion during an oral glucose tolerance test in preclinical models of diabetes mellitus [1].…”

Section: Introductionmentioning

confidence: 99%

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The pharmacokinetics of PF‐734200, a DPP‐IV inhibitor, in subjects with renal insufficiency

Dai

Johnson

Terra

et al. 2011

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Data demonstrating the pharmacokinetics (PK), efficacy and tolerability of PF‐734200, a potent DPP‐IV inhibitor in subjects with normal renal function, have been published or presented. WHAT THIS STUDY ADDS • This study provides better data on the PK of PF‐734200 in subjects with varying degrees of renal insufficiency and in subjects with end‐stage renal disease undergoing haemodialysis. In assessing the effects of renal impairment on the PK of PF‐734200, this study provides evidence for potential dose adjustment of PF‐734200 in patients with certain categories of renal impairment. AIMS PF‐734200 is a potent, selective inhibitor of DPP‐IV. This two‐part study evaluated the pharmacokinetics (PK) of oral 20 mg PF‐734200 in subjects with varying degrees of renal insufficiency or with end‐stage renal disease (ESRD) requiring chronic haemodialysis (HD). The study also assessed the HD clearance of PF‐734200 in ESRD. METHODS Part 1 included subjects with normal renal function or renal insufficiency but not on HD. Subjects received a single dose of 20 mg PF‐734200 while fasting and serum and urine samples were collected. In part 2, period 1, 1 h after HD, a single 20‐mg dose was given to subjects with ESRD and serum samples were collected. After a 7‐day washout, subjects received another dose followed by collection of serum samples (period 2), during which HD was initiated 4 h after dosing. Dialysate samples were collected to quantify amount of drug removed, from which HD clearance was calculated. The fraction of drug dialysed was calculated using an AUC‐based method. RESULTS Systemic exposures of PF‐734200 increased approximately 1.5‐, 2.2‐, 2.1‐ and 2.8‐fold in subjects with mild, moderate, or severe renal insufficiency or ESRD, respectively, compared with subjects with normal renal function. The terminal half‐life increased from 16.2 h in subjects with normal renal function to 36.6 h in subjects with ESRD. Approximately, 29% of PF‐734200 in the body after a single‐dose administration was dialysed by 4 h HD. CONCLUSIONS Systemic exposure of PF‐734200 increases with decreasing renal function. The effect of HD on drug removal is modest.

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Section: Figuresupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

The pharmacokinetics of PF‐734200, a DPP‐IV inhibitor, in subjects with renal insufficiency

Dai

Johnson

Terra

et al. 2011

Brit J Clinical Pharma

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“…The studied compounds were drawn with Chemsketch software (version 3.5) and saved as MDL‐molfiles, and finally converted to PDB format with Open Babel GUI (version 2.4.1). The crystal structure of DPP‐IV (PDB: 3F8S; resolution 2.0 Å) (Ammirati et al, ) was obtained from RCSB‐protein databank, wherein the water molecules were excluded from target proteins, and Swiss‐PdbViewer (SPDBV v4.1.0) was utilized for the energy minimization of enzyme. Molecular docking studies of the ligands were performed to evaluate the optimum binding modes between the DPP‐IV active sites and the studied metabolites.…”

Section: Methodsmentioning

confidence: 99%

First report of chromenyl derivatives from spineless marine cuttlefish Sepiella inermis : Prospective antihyperglycemic agents attenuate serine protease dipeptidyl peptidase‐IV

2019

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Spineless marine cuttlefish Sepiella inermis has been considered as a popular dietary cephalopod species in Asian and Mediterranean coasts. Bioassay‐directed purification of organic extract of S. inermis ensued in the characterization of two chromenyl derivatives. The studied compounds exhibited significantly greater antioxidant potencies (IC50 ≤ 0.5 mg/ml) when compared with α‐tocopherol. The substituted 1H‐isochromenyloxy‐11‐hydroxyethyl pentanoate isoform (compound 1) efficiently inhibited the carbolytic enzymes along with key regulator of insulin secretion dipeptidyl peptidase‐IV (IC50 0.16 mg/ml). The molecular docking simulations displayed optimum binding affinity of the compound 1 (−10.01 kcal/mol) with dipeptidyl peptidase‐IV and lesser inhibition constant (Ki 46.41 nM), which along with its permissible hydrophobic‐hydrophilic balance (log Pow ~ 2) appeared to play significant roles in its greater antihyperglycemic activity compared to other studied chromenyl isoform. The greater antioxidant and antidiabetic properties of compound 1 could be utilized as an important natural lead against hyperglycemic‐related disorders. Practical applications The edible spineless marine cuttlefish Sepiella inermis are ubiquitously available in Asian and Mediterranean coasts. The sequential chromatographic purification of the organic extract of S. inermis led to the identification of two pure chromenyl chemotypes. The metabolites with substituted 1H‐isochromenyloxy‐11‐hydroxyethyl pentanoate isoform (compound 1) displayed potential antioxidative and antihyperglycemic activities compared to the chemotype (2) bearing 3H‐isochromen‐5‐yl moiety. The attenuating potential of chromenyl chemotype 1 against carbohydrate hydrolyzing enzymes and insulin secretion regulator attributed towards its efficiency as an important natural lead against postprandial hyperglycemia and incretin hormone regulation to maintain glucose homeostasis in the biological system. The chromenyl metabolites isolated from S. inermis could be utilized as a functional food ingredient in the nutraceutical formulations against hyperglycemic‐related disorders.

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“…All molecules were generated and minimized using SYBYL 7.3, Tripos e . The protein receptor was obtained from the worldwide Protein Data Bank (PDB ID: 3F8S) (24) and processed by removing all solvents, adding hydrogens, and carrying out minimal minimization with the OPLS2001 force field using protein preparation wizard f . The grid was sized to 15 Å in each direction and centered using the original small‐molecule inhibitor.…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, Structure–Activity Relationships, and Docking Studies of 1‐(γ‐1,2,3‐Triazol Substituted Prolyl)‐(S)‐3,3‐Difluoropyrrolidines as a Novel Series of Potent and Selective Dipeptidyl Peptidase‐4 Inhibitors

Zhang

et al. 2012

Chem Biol Drug Des

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Dipeptidyl peptidase-4 inhibitors hold great potential for the treatment of type 2 diabetes. A series of 1-(γ-1,2,3-triazol substituted prolyl)-(S)-3,3-difluoropyrrolidines were designed, synthesized, and evaluated as novel dipeptidyl peptidase-4 inhibitors. Most of the compounds exhibited good in vitro potency against dipeptidyl peptidase-4. Among these, compounds 7j, 7q, and 7s displayed good dipeptidyl peptidase-4 activity and excellent selectivity versus other proteases including dipeptidyl peptidase-8, dipeptidyl peptidase-9, and FAP. The possible binding modes of compounds 7j, 7q, and 7s with dipeptidyl peptidase-4 were also explored by molecular docking simulation.

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(3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: A potent, selective, orally active dipeptidyl peptidase IV inhibitor

Cited by 37 publications

References 22 publications

The pharmacokinetics of PF‐734200, a DPP‐IV inhibitor, in subjects with renal insufficiency

The pharmacokinetics of PF‐734200, a DPP‐IV inhibitor, in subjects with renal insufficiency

First report of chromenyl derivatives from spineless marine cuttlefish Sepiella inermis : Prospective antihyperglycemic agents attenuate serine protease dipeptidyl peptidase‐IV

Design, Synthesis, Structure–Activity Relationships, and Docking Studies of 1‐(γ‐1,2,3‐Triazol Substituted Prolyl)‐(S)‐3,3‐Difluoropyrrolidines as a Novel Series of Potent and Selective Dipeptidyl Peptidase‐4 Inhibitors

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