Abstract：
:The use of deuteration in medicinal chemistry has exploded in the past years, and the FDA has recently approved the first deuterium-labeled drug. Precision deuteration goes beyond the pure and simple amelioration of the pharmacokinetic parameters of a drug and might provide an opportunity when facing problems in terms of metabolism-mediated toxicity, drug interactions, and low bioactivation. The use of deuterium is even broader, offering the opportunity to lower the degree of epimerization, reduce the dose of coadministered boosters, and discover compounds where deuterium is the basis for the mechanism of action. Nevertheless, designing, synthesizing, and developing a successful deuterated drug is far from straightforward, and the translation from concept to practice is often unpredictable. This Perspective provides an overview of the recent developments of deuteration, with a focus on deuterated clinical candidates, and highlights both opportunities and challenges of this strategy.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Pirali T,Serafini M,Cargnin S,Genazzani AAdoi
10.1021/acs.jmedchem.8b01808subject
Has Abstractpub_date
2019-06-13 00:00:00pages
5276-5297issue
11eissn
0022-2623issn
1520-4804journal_volume
62pub_type
杂志文章,评审abstract：:Melanin concentrating hormone (MCH) is involved in regulation of food intake and energy homeostasis. Antagonists of the MCH receptor are expected to affect food intake and weight gain, making MCH-R1 an attractive target for obesity treatment. Herein, we report the discovery of a novel, orally active series of MCH-R1 a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049035q
更新日期：2005-04-07 00:00:00
abstract：:In a previous study, we described affinity labeling of the lamb uterine estrogen receptor by 17 alpha-[(bromoacetoxy)alkyl/alkynyl]estradiols. However, the intrinsic receptor-alkylating activities of these compounds were probably very hampered by their poor hydrolytic stability in estrogen receptor-containing tissue e...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00013a011
更新日期：1995-06-23 00:00:00
abstract：:The syntheses and antiinflammatory assays of some dibenztroponeacetic and -propionic acids and derivatives are described. The most potent compound, d-2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, has a potency of ca, 70 times phenylbutazone in the rat carrageenan paw assay and two to three times indomethacin...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00222a004
更新日期：1977-12-01 00:00:00
abstract：:H(3) receptor antagonists based on a 2-aminoethylbenzofuran skeleton have been discovered, which are potent in vitro at human and rat H(3) receptors, with K(i) values of 0.1-5.8 nM. Analogues were discovered with potent (0.01-1 mg/kg) cognition and attention enhancing properties in animal models. One compound in parti...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm040118g
更新日期：2005-01-13 00:00:00
abstract：:Anaplastic lymphoma kinase (ALK) is a valid target for anticancer therapy; however, potent ALK inhibitors suitable for clinical use are lacking. Because the majority of described kinase inhibitors bind in the ATP pocket of the kinase domain, we have characterized this pocket in ALK using site-directed mutagenesis, inh...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060380k
更新日期：2006-09-21 00:00:00
abstract：:A novel series of 2-[(2,3-dihydro-1H-indol-1-yl)methyl]melatonin analogues has been prepared to probe the steric and electronic properties of the binding pocket of the MT(2) receptor accommodating the "out-of-plane" substituent of MT(2)-selective antagonists. The acetamide (6b) bearing an usubstituted indoline moiety ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800974d
更新日期：2009-02-12 00:00:00
abstract：:Dequalinium (4) is a potent and selective blocker of small conductance Ca2+-activated K+ channels, an important but relatively little studied class. The 4-NH2 group of dequalinium has been shown to contribute significantly to blocking potency. In this study, we have investigated further the role of the 4-NH2 group. Re...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00018a013
更新日期：1995-09-01 00:00:00
abstract：:The directional properties of hydrogen bonds play a major role in determining the specificity of intermolecular interactions. An energy function which takes explicit account of these properties has been developed for use in the determination of energetically favorable ligand binding sites on molecules of known structu...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00053a018
更新日期：1993-01-08 00:00:00
abstract：:Fatty acid synthase (FAS) is necessary for growth and survival of tumor cells and is a promising drug target for oncology. Here, we report on the syntheses and activity of novel inhibitors of the thioesterase domain of FAS. Using the structure of orlistat as a starting point, which contains a beta-lactone as the centr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800321h
更新日期：2008-09-11 00:00:00
abstract：:Spirocyclic scaffolds are incorporated in various approved drugs and drug candidates. The increasing interest in less planar bioactive compounds has given rise to the development of synthetic methodologies for the preparation of spirocyclic scaffolds. In this Perspective, we summarize the diverse synthetic routes to o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01473
更新日期：2021-01-14 00:00:00
abstract：:The dipeptide D-alanyl-D-alanine is an essential precursor of bacterial peptidoglycan; thus, blocking its formation is a possible target for the design of novel antibacterial agents. The synthesis of this dipeptide by bacterial D-alanine:D-alanine ligase requires ATP. In analogy with glutamine synthetase, we hypothesi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00128a033
更新日期：1989-08-01 00:00:00
abstract：:There is reported the first four members of heteroarotinoids, the names of which are ethyl (E)-p-[2-(4,4-dimethylthiochroman-6-yl)propenyl]benzoate (1b), ethyl (E)-p-[2-(4,4-dimethylchroman-6-yl)propenyl]benzoate (1c), ethyl (E)-p-[2-(4,4-dimethyl-1-oxothiochroman-6-yl)propenyl]benzoate (1d), and (E)-p-[2-(4,4-dimethy...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00379a021
更新日期：1985-01-01 00:00:00
abstract：:The intense intrinsic fluorescence emissions from several clinically relevant camptothecin drugs have been exploited in order to study the structural basis of drug binding to human serum albumin. Both HPLC and time-resolved fluorescence spectroscopic methodologies were employed to characterize the associations of camp...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00027a005
更新日期：1994-01-07 00:00:00
abstract：:The dynorphin (Dyn) A analogue zyklophin ([N-benzyl-Tyr(1)-cyclo(d-Asp(5),Dap(8))]dynorphin A(1-11)NH2) is a kappa opioid receptor (KOR)-selective antagonist in vitro, is active in vivo, and antagonizes KOR in the CNS after systemic administration. Hence, we synthesized zyklophin analogues to explore the structure-act...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501827k
更新日期：2015-11-25 00:00:00
abstract：:Plasmodium falciparum lactate dehydrogenase (pfLDH) is a key enzyme for energy generation of malarial parasites and is a potential antimalarial chemotherapeutic target. It is known that the oxamate moiety, a pyruvate analog, alone shows higher inhibition against pfLDH than human LDHs, suggesting that it can be used fo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070336k
更新日期：2007-08-09 00:00:00
abstract：:A series of (substituted amino)-1,2,4-benzothiadiazine 1-oxides has been synthesized and most members of the series have been shown to have blood pressure lowering effects in normotensive rabbits and in spontaneously hypertensive rats. The most active member of the series was 3-[4-(2-furoyl)-1-piperazinyl]-6,7-dimetho...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00181a003
更新日期：1980-07-01 00:00:00
abstract：:In the past few years the focus on central acetylcholine receptors has shifted from compounds with affinity for muscarinic acetylcholine receptors (mAChR) to compounds with affinity for nicotinic acetylcholine receptors (nAChR). The therapeutic potential includes treatment of a variety of diseases, e.g., Alzheimer's d...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990973d
更新日期：2000-06-01 00:00:00
abstract：:Several N(1)-arylalkylpolyamines containing various aromatic ring systems were synthesized as their respective HCl salts. The N(1)-substituents evaluated ranged in size from N(1)-benzyl, N(1)-naphthalen-1-ylmethyl, N(1)-2-(naphthalen-1-yl)ethyl, N(1)-3-(naphthalen-1-yl)propyl, N(1)-anthracen-9-ylmethyl, N(1)-2-(anthra...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0497040
更新日期：2004-11-18 00:00:00
abstract：:A series of new 9-phenanthrene amino alcohols has been prepared in which each compound bears from one to five halogen or halogen-containing moieties. A number of these compounds are extremely active against Plasmodium berghei in the mouse. Some structural requirements for optimal efficacy are considered. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00244a012
更新日期：1975-10-01 00:00:00
abstract：:Fragment optimizations in nearly 150 fragment-based drug discovery programs reported in the literature during the past fifteen years were investigated. By analyzing physicochemical properties and ligand efficiency indices we found that biochemical detection methods yield hits with superior ligand efficiency and lipoph...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm301851v
更新日期：2013-03-28 00:00:00
abstract：:Cdc7 serine/threonine kinase is a key regulator of DNA synthesis in eukaryotic organisms. Cdc7 inhibition through siRNA or prototype small molecules causes p53 independent apoptosis in tumor cells while reversibly arresting cell cycle progression in primary fibroblasts. This implies that Cdc7 kinase could be considere...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100504d
更新日期：2010-10-28 00:00:00
abstract：:A total of 53 N-benzoylated phenoxazines and phenothiazines, including their S-oxidized analogues, were synthesized and evaluated for antiproliferative activity, interaction with tubulin, and cell cycle effects. Potent inhibitors of multiple cancer cell lines emerged with the 10-(4-methoxybenzoyl)-10H-phenoxazine-3-ca...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200436t
更新日期：2011-06-23 00:00:00
abstract：:Elevated plasma levels of low-density lipoprotein (LDL) cholesterol are a major risk factor for atherosclerosis leading to coronary artery disease (CAD), which remains the main cause of mortality in Western society. We believe that by preventing the reabsorption of bile acids, a minimally absorbed apical sodium-codepe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm040215+
更新日期：2005-09-08 00:00:00
abstract：:Selective inhibitors of human sirtuin 2 (SIRT2), a deacetylase, are candidate therapeutic agents for neurodegenerative diseases such as Parkinson's disease and Huntington's disease as well as potential tools for elucidating the biological functions of SIRT2. On the basis of homology models of SIRT1 and SIRT2, we desig...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm3002108
更新日期：2012-06-28 00:00:00
abstract：:A novel lysine-based trifunctional chelate 3 was designed, synthesized, and characterized and bears both a chelating moiety (CHX-A' ') for sequestering radiometals (86Y or 111In) and the near-infrared dye Cy5.5 for dual modality PET (or SPECT) and fluorescence imaging, respectively. Successful conjugation of 3 to the ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070657w
更新日期：2007-09-20 00:00:00
abstract：:As a continuation of our project aimed at the search for new and safe chemotherapeutic and chemoprophylactic agents against American trypanosomiasis (Chagas' disease), several drugs structurally related to 4-phenoxyphenoxyethyl thiocyanate (4) were designed, synthesized, and evaluated as antiproliferative agents again...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0201518
更新日期：2002-08-29 00:00:00
abstract：:Guanidinothiazolecarboxamides (GTCs) are a novel class of antitumor agents found to be systemically active against experimental pulmonary metastases of 3LL Lewis lung carcinoma. A series of substituted benzothiazole GTCs were found to produce enhancement of survival in this model by using 8 days of intraperitoneal dos...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00111a009
更新日期：1991-07-01 00:00:00
abstract：:The E and Z isomers of 2-[2-(3-chlorophenyl)-1-phenyl-1-propenyl]pyridine (2a,b) and 2-[2-(3-chlorophenyl)-1-(4-hydroxyphenyl)-1-propenyl]pyridine (4a,b) were synthesized and separated as possible metabolites of 1-(3-chlorophenyl)-1-methyl-2-phenyl-2-(2-pyridine)ethanol (1a). Following administration of 1a to rats, a ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00200a017
更新日期：1978-02-01 00:00:00
abstract：:Antagonism of mercaptopropionic acid (MPA) induced convulsions, reflecting a GABAergic mechanism, was observed in a series of 1-aryl-3-(aminoalkylidene)oxindoles. Optimal MPA antagonism was associated with 3-halo, 3-alkyl, and/or 4-alkoxy substituents in the pendant aryl ring and with (dimethylamino)methylene, 1-(dime...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00122a025
更新日期：1989-02-01 00:00:00
abstract：:Bufotenine (5-hydroxy-N,N-dimethyltryptamine) has been reported to be behaviorally inactive or only very weakly active in man and animals; this may be a consequence of its low partition coefficient and resultant inability to penetrate the blood--brain barrier. The acetyl, propionyl, butyryl, isobutyryl, and pivalyl es...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00197a025
更新日期：1979-11-01 00:00:00
