Pei Z

References (12)

Title : Targeting alpha7 nicotinic acetylcholine receptors and their protein interactions in Alzheimer's disease drug development - Burns_2023_Drug.Dev.Res__
Author(s) : Burns LH , Pei Z , Wang HY
Ref : Drug Dev Res , : , 2023
Abstract : The decades-old cholinergic hypothesis of Alzheimer's disease (AD) led to clinical testing and FDA approval of acetylcholinesterase inhibitor drugs. Subsequently, the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) was proposed as a new drug target for enhancing cholinergic neurotransmission. Nearly simultaneously, soluble amyloid beta(1-42) (Abeta(42) ) was shown to bind alpha7nAChR with picomolar affinity to activate kinases that hyperphosphorylate tau, the precursor to tau-containing tangles. Multiple biopharmaceutical companies explored alpha7nAChR as a drug target for AD, mostly to enhance neurotransmission. Directly targeting alpha7nAChR proved to be a drug development challenge. The ultra-high-affinity interaction between Abeta(42) and alpha7nAChR posed a significant hurdle for direct competition in the AD brain. The receptor rapidly desensitizes, undermining efficacy of agonists. Drug discovery approaches therefore included partial agonists and allosteric modulators of alpha7nAChR. After substantial effort, numerous drug candidates were abandoned due to lack of efficacy or drug-related toxicities. As alternatives, proteins interacting with alpha7nAChR were sought. In 2016, a novel nAChR regulator was identified, but no drug candidates have emerged from this effort. In 2012, the interaction of filamin A with alpha7nAChR was shown to be critical to Abeta(42) 's toxic signaling via alpha7nAChR, presenting a new drug target. The novel drug candidate simufilam disrupts the filamin A-alpha7nAChR interaction, reduces Abeta(42) 's high-affinity binding to alpha7nAChR, and suppresses Abeta(42) 's toxic signaling. Early clinical trials of simufilam showed improvements in experimental CSF biomarkers and indications of cognitive improvement in mild AD patients at 1 year. Simufilam is currently in phase 3 clinical trials as a disease-modifying treatment for AD.
ESTHER : Burns_2023_Drug.Dev.Res__
PubMedSearch : Burns_2023_Drug.Dev.Res__
PubMedID: 37291958

Title : The Impact of ABCB1 and CES1 Polymorphisms on Dabigatran Pharmacokinetics in Healthy Chinese Subjects - Liu_2021_Pharmgenomics.Pers.Med_14_477
Author(s) : Liu Y , Yang C , Qi W , Pei Z , Xue W , Zhu H , Dong M , Guo Y , Cong D , Wang F
Ref : Pharmgenomics Pers Med , 14 :477 , 2021
Abstract : Dabigatran is a novel direct oral anticoagulant agent, whose plasma concentration is closely related to bleeding risk. Genetic polymorphisms can affect the level of plasma dabigatran. The purpose of this study was to understand the relationship between dabigatran-related genes and the plasma level of dabigatran in healthy Chinese subjects after taking a single oral dose. This study was performed with a single-center, single-dose, randomized, open-label, and four-period crossover trial design under both fasting and fed conditions. A total of 106 eligible healthy subjects were enrolled in the study and 104 were genotyped. One-way analysis of variance (ANOVA) was used to compare pharmacokinetic parameters among different genotypes and linear regression was applied to explore the multiplicative interaction between variables. In this study, we found that the genotype frequencies of CES1 rs2244613 and CES1 rs8192935 were significantly different between Chinese and Caucasians, but the genotype frequencies of ABCB1 rs1045642 and ABCB1 rs4148738 were similar in both populations. CES1 rs8192935 were associated with the peak concentration of dabigatran. There was no significant gender difference in the exposure level of dabigatran. Furthermore, food significantly delayed the absorption of dabigatran but had little effect on C(max) and AUC(0-).
ESTHER : Liu_2021_Pharmgenomics.Pers.Med_14_477
PubMedSearch : Liu_2021_Pharmgenomics.Pers.Med_14_477
PubMedID: 33935512

Title : Two birds with one stone: The detection of nerve agents and AChE activity with an ICT-ESIPT-based fluorescence sensor - Meng_2020_J.Hazard.Mater_410_124811
Author(s) : Meng W , Pei Z , Wang Y , Sun M , Xu Q , Cen J , Guo K , Xiao K , Li Z
Ref : J Hazard Mater , 410 :124811 , 2020
Abstract : Nerve agents are among the world's deadliest poisons, and the target enzyme is acetylcholinesterase (AChE). To better diagnosis nerve agent poisonings, a reliable diagnostic method for both nerve agents and AChE is desirable. Herein, we synthesized a series of fluorescent sensors for both real nerve agents and acetylcholinesterase activity detection. Among these sensors, HBQ-AE exhibited a fast response rate (within 10 s for nerve agent and 8 min for AChE), good sensitivity (the limit of detection is 6 nM and 0.2 U/mL) and a high off/on contrast. To the best of our knowledge, HBQ-AE is the first fluorescence sensor for nerve agents and AChE activity detection. The fluorescent change of HBQ-AE from nonfluorescence to blue fluorescence (nerve agent) or orange fluorescence (AChE) by excitation at 365 nm can be easily observed with the naked eye. HBQ-AE was successfully applied to image nerve agents and AChE activity in living cells. Moreover, HBQ-AE is the vital member to construct a test paper that can be employed to detect and diagnose chemical warfare agents.
ESTHER : Meng_2020_J.Hazard.Mater_410_124811
PubMedSearch : Meng_2020_J.Hazard.Mater_410_124811
PubMedID: 33450470

Title : Decrease in the production of beta-amyloid by berberine inhibition of the expression of beta-secretase in HEK293 cells - Zhu_2011_BMC.Neurosci_12_125
Author(s) : Zhu F , Wu F , Ma Y , Liu G , Li Z , Sun Y , Pei Z
Ref : BMC Neurosci , 12 :125 , 2011
Abstract : BACKGROUND: Berberine (BER), the major alkaloidal component of Rhizoma coptidis, has multiple pharmacological effects including inhibition of acetylcholinesterase, reduction of cholesterol and glucose levels, anti-inflammatory, neuroprotective and neurotrophic effects. It has also been demonstrated that BER can reduce the production of beta-amyloid40/42, which plays a critical and primary role in the pathogenesis of Alzheimer's disease. However, the mechanism by which it accomplishes this remains unclear. RESULTS: Here, we report that BER could not only significantly decrease the production of beta-amyloid40/42 and the expression of beta-secretase (BACE), but was also able to activate the extracellular signal-regulated kinase1/2 (ERK1/2) pathway in a dose- and time-dependent manner in HEK293 cells stably transfected with APP695 containing the Swedish mutation. We also find that U0126, an antagonist of the ERK1/2 pathway, could abolish (1) the activation activity of BER on the ERK1/2 pathway and (2) the inhibition activity of BER on the production of beta-amyloid40/42 and the expression of BACE. CONCLUSION: Our data indicate that BER decreases the production of beta-amyloid40/42 by inhibiting the expression of BACE via activation of the ERK1/2 pathway.
ESTHER : Zhu_2011_BMC.Neurosci_12_125
PubMedSearch : Zhu_2011_BMC.Neurosci_12_125
PubMedID: 22152059

Title : From the bench to the bedside: dipeptidyl peptidase IV inhibitors, a new class of oral antihyperglycemic agents - Pei_2008_Curr.Opin.Drug.Discov.Devel_11_512
Author(s) : Pei Z
Ref : Curr Opin Drug Discov Devel , 11 :512 , 2008
Abstract : New therapeutic agents are needed to combat the ever-increasing prevalence of diabetes. The two incretins glucagon-like peptide-1 (7-36) (GLP-1(7-36)) amide and glucose-dependent insulinotropic peptide (GIP) are released from the small intestine in response to the ingestion of nutrients and regulate glucose homeostasis in a glucose-dependent fashion; however, the action of both incretins is terminated by the rapid N-terminal cleavage of two amino acid residues of GLP-1 and GIP by dipeptidyl peptidase-IV (DPP-IV). The preservation of active GLP-1 and GIP by inhibiting DPP-IV activity is an attractive strategy for the treatment of diabetes in patients who exhibit a reduced incretin response. This strategy has resulted in the launch of two DPP-IV inhibitor drugs; sitagliptin in North America, several European territories, and various other countries, and vildagliptin in the EU as well as various countries. This article provides an overview of the recent advances in and the lessons learned from the design of potent and selective small-molecule inhibitors of DPP-IV for the treatment of type 2 diabetes.
ESTHER : Pei_2008_Curr.Opin.Drug.Discov.Devel_11_512
PubMedSearch : Pei_2008_Curr.Opin.Drug.Discov.Devel_11_512
PubMedID: 18600568

Title : Discovery and structure-activity relationships of piperidinone- and piperidine-constrained phenethylamines as novel, potent, and selective dipeptidyl peptidase IV inhibitors - Pei_2007_J.Med.Chem_50_1983
Author(s) : Pei Z , Li X , von Geldern TW , Longenecker K , Pireh D , Stewart KD , Backes BJ , Lai C , Lubben TH , Ballaron SJ , Beno DW , Kempf-Grote AJ , Sham HL , Trevillyan JM
Ref : Journal of Medicinal Chemistry , 50 :1983 , 2007
Abstract : Dipeptidyl peptidase IV (DPP4) inhibitors are emerging as a new class of therapeutic agents for the treatment of type 2 diabetes. They exert their beneficial effects by increasing the levels of active glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are two important incretins for glucose homeostasis. Starting from a high-throughput screening hit, we were able to identify a series of piperidinone- and piperidine-constrained phenethylamines as novel DPP4 inhibitors. Optimized compounds are potent, selective, and have good pharmacokinetic profiles.
ESTHER : Pei_2007_J.Med.Chem_50_1983
PubMedSearch : Pei_2007_J.Med.Chem_50_1983
PubMedID: 17367123
Gene_locus related to this paper: human-DPP4

Title : Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit - Backes_2007_Bioorg.Med.Chem.Lett_17_2005
Author(s) : Backes BJ , Longenecker K , Hamilton GL , Stewart K , Lai C , Kopecka H , von Geldern TW , Madar DJ , Pei Z , Lubben TH , Zinker BA , Tian Z , Ballaron SJ , Stashko MA , Mika AK , Beno DW , Kempf-Grote AJ , Black-Schaefer C , Sham HL , Trevillyan JM
Ref : Bioorganic & Medicinal Chemistry Lett , 17 :2005 , 2007
Abstract : A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal.
ESTHER : Backes_2007_Bioorg.Med.Chem.Lett_17_2005
PubMedSearch : Backes_2007_Bioorg.Med.Chem.Lett_17_2005
PubMedID: 17276063
Gene_locus related to this paper: ratno-dpp4 , human-DPP4

Title : 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 - Madar_2006_J.Med.Chem_49_6416
Author(s) : Madar DJ , Kopecka H , Pireh D , Yong H , Pei Z , Li X , Wiedeman PE , Djuric SW , von Geldern TW , Fickes MG , Bhagavatula L , McDermott T , Wittenberger S , Richards SJ , Longenecker KL , Stewart KD , Lubben TH , Ballaron SJ , Stashko MA , Long MA , Wells H , Zinker BA , Mika AK , Beno DW , Kempf-Grote AJ , Polakowski J , Segreti J , Reinhart GA , Fryer RM , Sham HL , Trevillyan JM
Ref : Journal of Medicinal Chemistry , 49 :6416 , 2006
Abstract : Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.
ESTHER : Madar_2006_J.Med.Chem_49_6416
PubMedSearch : Madar_2006_J.Med.Chem_49_6416
PubMedID: 17034148
Gene_locus related to this paper: human-DPP4

Title : Discovery, structure-activity relationship, and pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors - Pei_2006_J.Med.Chem_49_3520
Author(s) : Pei Z , Li X , Longenecker K , von Geldern TW , Wiedeman PE , Lubben TH , Zinker BA , Stewart K , Ballaron SJ , Stashko MA , Mika AK , Beno DW , Long M , Wells H , Kempf-Grote AJ , Madar DJ , McDermott TS , Bhagavatula L , Fickes MG , Pireh D , Solomon LR , Lake MR , Edalji R , Fry EH , Sham HL , Trevillyan JM
Ref : Journal of Medicinal Chemistry , 49 :3520 , 2006
Abstract : A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar K(i)'s, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats.
ESTHER : Pei_2006_J.Med.Chem_49_3520
PubMedSearch : Pei_2006_J.Med.Chem_49_3520
PubMedID: 16759095
Gene_locus related to this paper: human-DPP4

Title : Crystal structures of DPP-IV (CD26) from rat kidney exhibit flexible accommodation of peptidase-selective inhibitors - Longenecker_2006_Biochemistry_45_7474
Author(s) : Longenecker KL , Stewart KD , Madar DJ , Jakob CG , Fry EH , Wilk S , Lin CW , Ballaron SJ , Stashko MA , Lubben TH , Yong H , Pireh D , Pei Z , Basha F , Wiedeman PE , von Geldern TW , Trevillyan JM , Stoll VS
Ref : Biochemistry , 45 :7474 , 2006
Abstract : Dipeptidyl peptidase IV (DPP-IV) belongs to a family of serine peptidases, and due to its indirect regulatory role in plasma glucose modulation, DPP-IV has become an attractive pharmaceutical target for diabetes therapy. DPP-IV inactivates the glucagon-like peptide (GLP-1) and several other naturally produced bioactive peptides that contain preferentially a proline or alanine residue in the second amino acid sequence position by cleaving the N-terminal dipeptide. To elucidate the details of the active site for structure-based drug design, we crystallized a natural source preparation of DPP-IV isolated from rat kidney and determined its three-dimensional structure using X-ray diffraction techniques. With a high degree of similarity to structures of human DPP-IV, the active site architecture provides important details for the design of inhibitory compounds, and structures of inhibitor-protein complexes offer detailed insight into three-dimensional structure-activity relationships that include a conformational change of Tyr548. Such accommodation is exemplified by the response to chemical substitution on 2-cyanopyrrolidine inhibitors at the 5 position, which conveys inhibitory selectivity for DPP-IV over closely related homologues. A similar conformational change is also observed in the complex with an unrelated synthetic inhibitor containing a xanthine core that is also selective for DPP-IV. These results suggest the conformational flexibility of Tyr548 is unique among protein family members and may be utilized in drug design to achieve peptidase selectivity.
ESTHER : Longenecker_2006_Biochemistry_45_7474
PubMedSearch : Longenecker_2006_Biochemistry_45_7474
PubMedID: 16768443
Gene_locus related to this paper: ratno-dpp4

Title : Discovery of ((4R,5S)-5-amino-4-(2,4,5- trifluorophenyl)cyclohex-1-enyl)-(3- (trifluoromethyl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (ABT-341), a highly potent, selective, orally efficacious, and safe dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes - Pei_2006_J.Med.Chem_49_6439
Author(s) : Pei Z , Li X , von Geldern TW , Madar DJ , Longenecker K , Yong H , Lubben TH , Stewart KD , Zinker BA , Backes BJ , Judd AS , Mulhern M , Ballaron SJ , Stashko MA , Mika AK , Beno DW , Reinhart GA , Fryer RM , Preusser LC , Kempf-Grote AJ , Sham HL , Trevillyan JM
Ref : Journal of Medicinal Chemistry , 49 :6439 , 2006
Abstract : Dipeptidyl peptidase IV (DPP4) deactivates glucose-regulating hormones such as GLP-1 and GIP, thus, DPP4 inhibition has become a useful therapy for type 2 diabetes. Optimization of the high-throughput screening lead 6 led to the discovery of 25 (ABT-341), a highly potent, selective, and orally bioavailable DPP4 inhibitor. When dosed orally, 25 dose-dependently reduced glucose excursion in ZDF rats. Amide 25 is safe in a battery of in vitro and in vivo tests and may represent a new therapeutic agent for the treatment of type 2 diabetes.
ESTHER : Pei_2006_J.Med.Chem_49_6439
PubMedSearch : Pei_2006_J.Med.Chem_49_6439
PubMedID: 17064063
Gene_locus related to this paper: human-DPP4

Title : Catalytic self-screening of cholinesterase substrates from a dynamic combinatorial thioester library -
Author(s) : Larsson R , Pei Z , Ramstrom O
Ref : Angew Chem Int Ed Engl , 43 :3716 , 2004
PubMedID: 15248281