Peptidyl α-Ketoamides with Nucleobases, Methylpiperazine, and Dimethylaminoalkyl Substituents as Calpain Inhibitors

Published on Aug 6, 2010in Journal of Medicinal Chemistry6.205
· DOI :10.1021/JM901221V
Asli Ovat2
Estimated H-index: 2
(Georgia Institute of Technology),
Zhao Zhao Li (Georgia Institute of Technology)+ 4 AuthorsJames C. Powers63
Estimated H-index: 63
A series of peptidyl α-ketoamides with the general structure Cbz-l-Leu-d,l-AA-CONH-R were synthesized and evaluated as inhibitors for the cysteine proteases calpain I, calpain II, and cathepsin B. Nucleobases, methylpiperazine, and dimethylaminoalkyl groups were incorporated into the primed region of the inhibitors to generate compounds that potentially cross the blood−brain barrier. Two of these compounds (Cbz-Leu-d,l-Abu-CONH-(CH2)3-adenin-9-yl and Cbz-Leu-d,l-Abu-CONH-(CH2)3-(4-methylpiperazin-1-yl) have been shown to have useful concentrations in the brain in animals. The best inhibitor for calpain I was Cbz-Leu-d,l-Abu-CONH-(CH2)3-2-methoxyadenin-9-yl (Ki = 23 nM), and the best inhibitor for calpain II was Cbz-Leu-d,l-Phe-CONH-(CH2)3-adenin-9-yl (Ki = 68 nM). On the basis of the crystal structure obtained with heterocyclic peptidyl α-ketoamides, we have improved inhibitor potency by introducing a small hydrophobic group on the adenine ring. These inhibitors have good potential to be used in the treat...
📖 Papers frequently viewed together
4 Authors (Chun Zhang, ..., Ning Jiao)
190 Citations
39 Citations
340 Citations
#1Mi-Hwa Kim (SNU: Seoul National University)H-Index: 4
#2Han-Joo Maeng (SNU: Seoul National University)H-Index: 10
Last. Suk-Jae Chung (SNU: Seoul National University)H-Index: 35
view all 8 authors...
Abstract The objective of this study was to characterize the mechanism that controls the transport of donepezil into the brain. The apparent brain uptake clearance (CL app,br ) was decreased as a function of the dose of donepezil, suggesting an involvement of a saturable transport process via transporter(s) in the penetration across the blood–brain barrier (BBB). Consistent with in vivo results, the uptake of substrates for organic cation transporters was significantly reduced by donepezil in bo...
38 CitationsSource
#1Seth A. Jones (University of Adelaide)H-Index: 3
#2Matthew A. JonesH-Index: 10
Last. Andrew D. AbellH-Index: 31
view all 6 authors...
A series of Val-Leu based peptidic aldehydes containing either a furan or thiophene at the Nterminus was prepared and assayed against ovine m-calpain. In general, potency is favoured by a 2- substituted (rather than 3-substituted) heterocycle, a thiophene rather than a furan, and a shorter chain length at the N-terminus. Molecular docking experiments provide some rationale for these observations.
3 CitationsSource
#1Kavitha S. Rao (Cleveland Clinic)H-Index: 8
#2Anuja Ghorpade (UNT: University of North Texas)H-Index: 31
Last. Vinod Labhasetwar (Cleveland Clinic)H-Index: 63
view all 3 authors...
The development of antiretroviral drugs over the past couple of decades has been commendable owing to the identification of several new targets within the overall HIV replication cycle. However, complete control over HIV/AIDS is yet to be achieved. This is because the current anti-HIV drugs, although effective in reducing plasma viral levels, cannot eradicate the virus completely from the body. This occurs because most anti-HIV drugs do not accumulate in certain cellular and anatomical reservoir...
69 CitationsSource
#1Suk-Yul Jung (Wonkwang University)H-Index: 2
#2Bing Zheng (Wonkwang University)H-Index: 3
Last. Hyun Park (Wonkwang University)H-Index: 21
view all 7 authors...
The biological understanding of malaria parasites has increased considerably over the past two decades with the discovery of many potential targets for the development of new antimalarial drugs. Calpain, a cysteine protease of Plasmodium falciparum, is believed to be a central mediator essential for parasitic activity. However, the utility of calpain as a potential anti-malarial target in P. falciparum has not been fully determined. In the present study, we determined the effect of N-acetyl-L-Le...
9 CitationsSource
#1Lavanya Varatharajan (St George's Hospital)H-Index: 2
#2Sarah A. Thomas ('KCL': King's College London)H-Index: 27
The advent of highly active antiretroviral therapy (HAART), which constitutes HIV protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors, has dramatically reduced the morbidity and mortality associated with human immunodeficiency virus (HIV) infection in resource-rich countries. However, this disease still kills several million people each year. Though the reason for therapeutic failure is ...
170 CitationsSource
#1Ming SunH-Index: 6
#2Yumei ZhaoH-Index: 6
Last. Chao XuH-Index: 6
view all 4 authors...
In vitro nitric oxide (NO) regulates calpain and caspase-3 activation, and in vivo neuronal nitric oxide synthase (nNOS), calpain and caspase-3 participate in the ischemic brain injury. Our objective was to investigate whether nNOS was involved in the ischemic brain injury through activating calpain and caspase-3 during experimental stroke. Rats received 1-h ischemia by intraluminant filament, and then reperfused for 23 h (R 23 h). nNOS inhibitor 7-nitroindozale (7-NI, 50 mg/kg) was administrate...
55 CitationsSource
#1Na-Young Lee (Sookmyung Women's University)H-Index: 10
#2H.-M. Choi (Sookmyung Women's University)H-Index: 1
Last. Young-Sook Kang (Sookmyung Women's University)H-Index: 27
view all 3 authors...
Abstract Choline is an essential nutrient for phospholipids and acetylcholine biosynthesis in normal development of fetus. In the present study, we investigated the functional characteristics of choline transport system and inhibitory effect of cationic drugs on choline transport in rat conditionally immortalized syncytiotrophoblast cell line (TR-TBT). Choline transport was weakly Na + dependent and significantly influenced by extracellular pH and by membrane depolarization. The transport proces...
15 CitationsSource
#1Ryan M. Franke (St. Jude Children's Research Hospital)H-Index: 15
#2Lisa A. Scherkenbach (St. Jude Children's Research Hospital)H-Index: 1
Last. Alex SparreboomH-Index: 104
view all 3 authors...
The solute carrier, human organic anion transporting polypeptide 1A2 (OATP1A2, OATP-A, OATP1 and OATP) is highly expressed in the intestine, kidney, cholangiocytes and the blood–brain barrier. This localization suggests that OATP1A2 may be vitally important in the absorption, distribution and excretion of a broad array of clinically important drugs. Several nonsynonymous polymorphisms have been identified in the gene encoding OATP1A2, SLCO1A2 (SLC21A3), with some of these variants demonstrating ...
51 CitationsSource
#1Ki Yong Lee (Kyung Hee University)H-Index: 3
#2Kwang Seob Lee (KIST: Korea Institute of Science and Technology)H-Index: 3
Last. Yong Sup Lee (Kyung Hee University)H-Index: 21
view all 4 authors...
Abstract Excessive calpain activation contributes to serious cellular damage in many pathological conditions. The involvement of μ-calpain in neurological disorders such as, stroke and Alzheimer's disease has attracted considerable interest in the use of calpain inhibitors as therapeutic agents. 6-Pyridone 2-carboxamides derived from ketoamides were synthesized as conformationally constrained structures resembling the well known peptidic μ-calpain inhibitor, MDL 28,170, and their μ-calpain inhib...
6 CitationsSource
#1Andrew D. Abell (University of Adelaide)H-Index: 31
#2Matthew A. Jones (Cant.: University of Canterbury)H-Index: 10
Last. Roy Bickerstaffe (Canterbury of New Zealand)H-Index: 23
view all 12 authors...
The design and elaboration of a series of macrocyclic templates that exhibit a propensity to adopt a β-strand-like peptide-backbone conformation led to potent and selective inhibitors of calpain 2. Macrocycle 1 retarded calcium-induced opacification in an ovine-lens culture assay and is a lead compound for the development of a drug for cataract treatment. Cbz=carbobenzyloxy.
62 CitationsSource
Cited By23
#1Jianbo Liu (UCSF: University of California, San Francisco)
#2Matthew F.L. Parker (UCSF: University of California, San Francisco)H-Index: 9
Last. David M. Wilson (UCSF: University of California, San Francisco)H-Index: 26
view all 6 authors...
Summary null null Found in biomolecules, pharmaceuticals, and agrochemicals, amide-containing molecules are ubiquitous in nature, and their derivatization represents a significant methodological goal in fluorine chemistry. Trifluoromethyl amides have emerged as important functional groups frequently found in pharmaceutical compounds. To date, there is no strategy for synthesizing N-trifluoromethyl amides from abundant organic carboxylic acid derivatives, which are ideal starting materials in ami...
#1Snehasis Banerjee (Government College of Engineering and Leather Technology)H-Index: 10
The search for therapeutic drugs that can neutralize the effects of COVID-2019 (SARS-CoV-2) infection is the main focus of current research. The coronavirus main protease (Mpro) is an attractive target for anti-coronavirus drug design. Further, α-ketoamide is proved to be very effective as a reversible covalent-inhibitor against cysteine proteases. Herein, we report on the non-covalent to the covalent adduct formation mechanism of α-ketoamide-based inhibitor with the enzyme active site amino aci...
2 CitationsSource
#1Levente E. Dókus (ELTE: Eötvös Loránd University)H-Index: 4
#2Mo'ath Yousef (ELTE: Eötvös Loránd University)H-Index: 1
Last. Zoltán Bánóczi (ELTE: Eötvös Loránd University)H-Index: 10
view all 3 authors...
ABSTRACTIntroduction: Calpains are intracellular Ca2+-dependent cysteine proteases with 15 known members in the enzyme family. They act as regulatory enzymes, their cleavage modifying the function ...
7 CitationsSource
#1Aparna Monga (IITR: Indian Institute of Technology Roorkee)H-Index: 4
#2Sourav Bagchi (IITR: Indian Institute of Technology Roorkee)H-Index: 10
Last. Anuj Sharma (IITR: Indian Institute of Technology Roorkee)H-Index: 20
view all 3 authors...
7 CitationsSource
#1Dácil Hernández (CSIC: Spanish National Research Council)H-Index: 15
#2Alicia Boto (CSIC: Spanish National Research Council)H-Index: 20
Last. Eleuterio Álvarez (CSIC: Spanish National Research Council)H-Index: 50
view all 4 authors...
An efficient, metal-free synthesis of unusual α-keto γ-amino esters from α-amino acids is achieved by a radical scission–oxidation–addition of silyloxy acrylates procedure, where no purification of the reaction intermediates is needed. This protocol can be applied to the selective modification of the C-terminal position in peptides to give α,γ-hybrids.
4 CitationsSource
#1Mani Ramanathan (NTU: National Taiwan University)H-Index: 6
#2Chun-Kai Kuo (NTU: National Taiwan University)H-Index: 1
Last. Shiuh-Tzung Liu (NTU: National Taiwan University)H-Index: 34
view all 3 authors...
One-pot and metal free synthesis of α-ketoamides has been described through in situ generation of aryl ketones from easily available ethylarenes followed by amidation with various amines. This multiple oxidation protocol involves catalytic I2–pyridine–TBHP (t-butyl hydroperoxide) mediated oxidative benzylic carbonylation and sequential NaI–TBHP mediated oxidative amidation without using any solvent.
12 CitationsSource
#1Chengkou LiuH-Index: 8
#2Zhao Yang (CPU: China Pharmaceutical University)H-Index: 11
Last. Kai Guo (Nanjing Tech University)H-Index: 20
view all 8 authors...
An efficient copper–TEMPO-catalyzed one-pot synthesis of α-ketoamides from phenethyl alcohol derivatives was developed firstly. Moreover, molecular oxygen in open air was employed as the oxidant with a broad substrate scope, which makes this methodology more practical. Based on some control experiments, a plausible mechanism was proposed.
12 CitationsSource
#1Yogesh Kumar (IITP: Indian Institute of Technology Patna)H-Index: 6
#2Mukta Shaw (IITP: Indian Institute of Technology Patna)H-Index: 4
Last. Amit Kumar (IITP: Indian Institute of Technology Patna)H-Index: 17
view all 4 authors...
A simple and straightforward method for the synthesis of primary α-ketoamides has been discovered. The reaction represents the first example of benzylimidates directly converting to primary α-ketoamides by using sustainable molecular oxygen as an oxidant. This reaction proceeds in the presence of copper(II) salt via cleavage of benzylic C–H and C–O bonds of the benzylimidates with liberation of alcohols as the only byproduct. A wide substrate scope, operationally mild conditions, the use of sing...
33 CitationsSource
#1Xueyao Zhang (Lanzhou University)H-Index: 9
#2Honglei Yang (Lanzhou University)H-Index: 19
Last. Jiantai Ma (Lanzhou University)H-Index: 59
view all 6 authors...
An efficient catalyst based on the cage-like mesoporous material SBA-16 as the support and Cu(I) as active sites has been successfully prepared. The catalyst demonstrated high catalytic activity (up to 88%) in the direct oxidative synthesis of α-ketoamides between acetophenone and piperidine, employing O2 from open air as the oxidant without other additives. A heterogeneous catalyst was applied in this reaction for the first time, and the catalyst could be easily separated from the reaction syst...
18 CitationsSource
#1Chengkou LiuH-Index: 8
#2Zheng FangH-Index: 18
Last. Kai GuoH-Index: 20
view all 6 authors...
A practical two-step synthesis of α-ketoamides and α-amino ketones via direct oxidative coupling between 2° benzylic alcohols and amines was developed. Hydrogen peroxide, an economic and environmentally friendly oxidant, was used, and a metal catalyst was unnecessary. Moreover, the continuous-flow technique was employed to increase the functional group tolerance, efficiency and safety.
17 CitationsSource