Abstract：
:Catechol O-methyltransferase (COMT) is the enzyme responsible for the O-methylation of endogenous neurotransmitters and of xenobiotic substances and hormones incorporating catecholic structures. COMT is a druggable biological target for the treatment of various central and peripheral nervous system disorders, including Parkinson's disease, depression, schizophrenia, and other dopamine deficiency-related diseases. The purpose of this perspective is fourfold: (i) to summarize the physiological role of COMT inhibitors in central and peripheral nervous system disorders; (ii) to provide the history and perspective of the medicinal chemistry behind the discovery and development of COMT inhibitors; (iii) to discuss how the physicochemical properties of recognized COMT inhibitors are understood to exert influence over their pharmacological properties; and (iv) to evaluate the clinical benefits of the most relevant COMT inhibitors.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Kiss LE,Soares-da-Silva Pdoi
10.1021/jm500572bsubject
Has Abstractpub_date
2014-11-13 00:00:00pages
8692-717issue
21eissn
0022-2623issn
1520-4804journal_volume
57pub_type
杂志文章abstract：:Several esters of beta-carboline-3-carboxylic acid were synthesized and tested in respect to their affinity for the benzodiazepine receptor in bovine cortex membranes. Out of these derivatives, the methyl, ethyl, and n-propyl ester were clearly the most potent, while the n-butyl, benzyl, and 3-pyridylmethyl ester were...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00358a008
更新日期：1983-04-01 00:00:00
abstract：:We previously reported (J. Med. Chem. 1993, 36, 1188-1193) that changes to the ring size of the piperidine and cyclohexyl rings of the high-affinity and selective dopamine (DA)-uptake inhibitor 1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidine (BTCP, 2) caused different, and in some cases opposite, changes in affinity for...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00077a011
更新日期：1993-12-10 00:00:00
abstract：:Acyl-CoA:cholesterol acyltransferase (ACAT) is the primary enzyme involved in intracellular cholesterol esterification. Arterial wall infiltration by macrophages and subsequent uncontrolled esterification of cholesterol leading to foam cell formation is believed to be an important process which leads to the developmen...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00007a004
更新日期：1995-03-31 00:00:00
abstract：:Modification of the 2(S)-methylbutyryl moiety of mevinolin led to a series of side chain ester derivatives. A systematic exploration of the structure-activity relationships showed that the introduction of an additional aliphatic group on the carbon alpha to the carbonyl group increased potency. This observation led to...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00155a040
更新日期：1986-05-01 00:00:00
abstract：:Anthraquinone derivatives related to the moderately potent, nonselective P2Y(12) receptor antagonist reactive blue 2 (6) have been synthesized and optimized with respect to P2Y(12) receptor affinity. A radioligand binding assay utilizing human blood platelet membranes and the P2Y(12) receptor-selective antagonist radi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9003297
更新日期：2009-06-25 00:00:00
abstract：:Two-bivalent ligands (P-X-P) containing the beta-naltrexamine pharmacophore (P) and a connecting oligoethylene glycol spanner (X) were synthesized and evaluated for narcotic antagonistic activity in the guinea pig ileum (GPI) and mouse vas deferens (MVD). The bivalent ligand 2 whose spanner contains three ethylene uni...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00349a016
更新日期：1982-07-01 00:00:00
abstract：:The receptor CRM1 is responsible for the nuclear export of many tumor-suppressor proteins and viral ribonucleoproteins. This renders CRM1 an interesting target for therapeutic intervention in diverse cancer types and viral diseases. Structural studies of Saccharomyces cerevisiae CRM1 ( Sc ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c00143
更新日期：2020-07-23 00:00:00
abstract：:In this paper, a peptide substrate (Pep8) of TSSK1 is identified. Using Pep8 as a substrate, two homogeneous and efficient assays for TSSK1 inhibitors screening have been developed, including luminescent kinase assay and LC-MS-based high-throughput assay. Two classes of compounds were identified that are able to effic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9002846
更新日期：2009-07-23 00:00:00
abstract：:Glutathione transferase omega-1 (GSTO1-1) is an enzyme whose function supports the activation of interleukin (IL)-1β and IL-18 that are implicated in a variety of inflammatory disease states for which small-molecule inhibitors are sought. The potent reactivity of the active-site cysteine has resulted in reported inhib...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01391
更新日期：2020-03-26 00:00:00
abstract：:Early studies in these laboratories of peptidomimetic structures containing a basic P1 moiety led to the highly potent and selective thrombin inhibitors 2 (Ki = 5.0 nM) and 3 (Ki = 0.1 nM). However, neither attains significant blood levels upon oral administration to rats and dogs. With the aim of improving pharmacoki...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9705014
更新日期：1998-01-29 00:00:00
abstract：:Novel classes of antimalarial drugs are needed due to emerging drug resistance. Azithromycin, the first macrolide investigated for malaria treatment and prophylaxis, failed as a single agent and thus novel analogues were envisaged as the next generation with improved activity. We synthesized 42 new 9a-N substituted 15...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm201615t
更新日期：2012-02-09 00:00:00
abstract：:Carbamate derivatives of bile acids were synthesized with the aim of systematically exploring the potential for farnesoid X receptor (FXR) modulation endowed with occupancy of the receptor's back door, localized between loops H1-H2 and H4-H5. Since it was previously shown that bile acids bind to FXR by projecting the ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060294k
更新日期：2006-07-13 00:00:00
abstract：:Farnesoid X receptor (FXR) agonists are emerging as important potential therapeutics for the treatment of nonalcoholic steatohepatitis (NASH) patients, as they exert positive effects on multiple aspects of the disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular inflammation, hepatic injury, an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01621
更新日期：2020-04-23 00:00:00
abstract：:We recently introduced sulfated pentagalloylglucopyranoside (SPGG) as an allosteric inhibitor of factor XIa (FXIa) (Al-Horani et al., J. Med Chem. 2013, 56, 867-878). To better understand the SPGG-FXIa interaction, we utilized eight SPGG variants and a range of biochemical techniques. The results reveal that SPGG's su...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500311e
更新日期：2014-06-12 00:00:00
abstract：:While adding the structural features that are more favored by on-target activity is the more common strategy in selectivity optimization, the opposite strategy of subtracting the structural features that contribute more to off-target activity can also be very effective. Reported here is our successful effort of improv...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00033
更新日期：2017-03-09 00:00:00
abstract：:Cationic amphiphiles derived from aminoglycosides (AGs) have been shown to exhibit enhanced antimicrobial activity. Through the attachment of hydrophobic residues such as linear alkyl chains on the AG backbone, interesting antibacterial and antifungal agents with a novel mechanism of action have been developed. Herein...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01375
更新日期：2015-12-10 00:00:00
abstract：:In an analogy to the potent catechol dopamine D1 agonists dihydrexidine (1) and dinapsoline (2), benzo rings were fused onto the structures of the dopamine D2-selective agonists quinelorane (3) and quinpirole (4). Each of the phenyl ring-substituted derivatives had significant affinity for D2 receptors, albeit somewha...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9804533
更新日期：1999-03-11 00:00:00
abstract：:A series of N-substituted 3-aminoglutarimides have been synthesized and tested for inhibitory activity against a range of chemokines in vitro and for suppression of lipopolysaccharide-induced inflammation in vivo. The results show that they represent the first class of small molecules with broad-spectrum chemokine inh...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010984i
更新日期：2002-01-17 00:00:00
abstract：:The enzyme phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28) catalyzes the final step in the biosynthesis of epinephrine and is a potential drug target, primarily for the control of hypertension. Unfortunately, many potent PNMT inhibitors also possess significant affinity for the a2-adrenoceptor, which compli...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01475
更新日期：2020-11-25 00:00:00
abstract：:A series of potent nonpeptide inhibitors of the HIV protease have been identified. Using the structure of compound 3 bound to the HIV protease, bis tertiary amide inhibitor 9 was designed and prepared. Compound 9 was found to be about 17 times more potent than 3, and the structure of the protein-ligand complex of 9 re...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960092w
更新日期：1996-07-05 00:00:00
abstract：:5-Nitronicotinamide (1) was prepared from 5-bromonicotinoyl chloride by treatment with ammonia and then oxidation with fuming H2SO4 and 30% H202. 2-Cholor-, 2-alkoxy-2-benzyloxy,2-phenoxy-,2-alkylamino-, and 2-benzylamino-5-nitronicatinamides were also prepared via 2-chloro-3-cyano-5-nitropyridine. 2-Methyl-5-nitronic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00211a027
更新日期：1977-01-01 00:00:00
abstract：:Most non-thiol CAAX-peptidomimetic farnesyltransferase inhibitors bear nitrogen-containing heterocycles in place of the terminal cysteine which are supposed to coordinate the enzyme-bound zinc. However, it has been shown that those nitrogen-containing heterocycles can be replaced by carbocyclic aromatic moieties which...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010873j
更新日期：2001-09-13 00:00:00
abstract：:Substitution at the ortho position of N-(3,4-dimethyl-5-isoxazolyl) benzenesulfonamide led to the identification of the biphenylsulfonamides as a novel series of endothelin-A (ETA) selective antagonists. Appropriate substitutions on the pendant phenyl ring led to improved binding as well as functional activity. A hydr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970872k
更新日期：1998-12-17 00:00:00
abstract：:A noninvasive topical ocular therapy for the treatment of neovascular or "wet" age-related macular degeneration would provide a patient administered alternative to the current standard of care, which requires physician administered intravitreal injections. This manuscript describes a novel strategy for the use of in v...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01731
更新日期：2018-02-22 00:00:00
abstract：:Alkenylidene bisphenols are prepared by condensation of an appropriate phenol with a haloacetaldehyde, followed by base-induced elimination, or by condensation of the corresponding aryl methyl ether, elimination, and deprotection of the phenol with boron tribromide. The resulting compounds may be further elaborated by...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00194a022
更新日期：1979-08-01 00:00:00
abstract：:Cell cycle experiments with our previously reported 4-biphenylaminoquinazoline (1-3) multityrosine kinase inhibitors revealed an activity profile resembling that of known tubulin polymerization inhibitors. Novel 4-biarylaminoquinazoline analogues of compound 2 were synthesized and evaluated as inhibitors of several ty...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500034j
更新日期：2014-06-12 00:00:00
abstract：:New transition-state analogues bearing C-termini derived from alpha-mercaptoalkanoic acids, esters, and amides were prepared and evaluated as inhibitors of human renin. Addition of alpha-mercaptoalkanoate esters to a chiral Boc-amino epoxide intermediate led ultimately to the target [(2R,3S)-3-(BocPheHis-amino)-4-cycl...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00093a009
更新日期：1992-07-24 00:00:00
abstract：:A series of 4-methyl-3-(arylthio)furoxans were synthesized by oxidation of 1-(arylthio)-2-methylglyoxymes with dinitrogen tetroxide. Reduction with trimethyl phosphite of the furoxan derivatives afforded the corresponding furazans, while oxidation with an equimolar amount of 30% hydrogen peroxide in acetic acid or wit...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00095a028
更新日期：1992-08-21 00:00:00
abstract：:Symmetrical and asymmetrical fluorinated phenyltriazolyl-thiodigalactoside derivatives have been synthesized and evaluated as inhibitors of galectin-1 and galectin-3. Systematic tuning of the phenyltriazolyl-thiodigalactosides' fluoro-interactions with galectin-3 led to the discovery of inhibitors with exceptional aff...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01626
更新日期：2018-02-08 00:00:00
abstract：:Novel heteroatom-incorporated antofine and cryptopleurine analogues were designed, synthesized, and tested against a panel of five cancer cell lines. Two new S-13-oxo analogues (11 and 16) exhibited potent cell growth inhibition in vitro (GI(50): 9 nM and 20 nM). Interestingly, both compounds displayed improved select...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200330s
更新日期：2011-07-28 00:00:00
