Abstract：
:The human brain is a uniquely complex organ, which has evolved a sophisticated protection system to prevent injury from external insults and toxins. Designing molecules that can overcome this protection system and achieve optimal concentration at the desired therapeutic target in the brain is a specific and major challenge for medicinal chemists working in CNS drug discovery. Analogous to the now widely accepted rule of 5 in the design of oral drugs, the physicochemical properties required for optimal brain exposure have been extensively studied in an attempt to similarly define the attributes of successful CNS drugs and drug candidates. This body of work is systematically reviewed here, with a particular emphasis on the interplay between the most critical physicochemical and pharmacokinetic parameters of CNS drugs as well as their impact on medicinal chemistry strategies toward molecules with optimal brain exposure. A summary of modern CNS pharmacokinetic concepts and methods is also provided.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Rankovic Zdoi
10.1021/jm501535rsubject
Has Abstractpub_date
2015-03-26 00:00:00pages
2584-608issue
6eissn
0022-2623issn
1520-4804journal_volume
58pub_type
杂志文章,评审abstract：:A series of 1-thia analogues of the pyrrolizine bis(carbamate) 9 (NSC-278214), namely 5-aryl-2,3-dihydropyrrolo-[2,1-b]thiazole-6,7-dimethanol 6,7-bis(isopropylcarbamates) (7a-d), were prepared by multistep syntheses from the proline analogue thiazolidine-2-carboxylic acid. The compounds were tested for growth inhibit...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00402a030
更新日期：1988-07-01 00:00:00
abstract：:A structure-activity study was carried out to determine the importance of the N-terminal amino acids of hCGRP8-37 in binding and antagonistic activity to CGRP receptors. Therefore, fragments of hCGRP8-37 as well as analogs obtained by the replacement of residues 9-12 by L-alanine were synthesized by solid-phase peptid...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00090a003
更新日期：1992-06-12 00:00:00
abstract：:The importance of steric factors in quantitative structure-activity relationships involving steroid hormones is discussed. a variety of steric parameters, such as parachlor, molecular volume, van der Waals volume, and including difference and squared steric terms, is explored in an attempt to find preferred forms for...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00228a002
更新日期：1976-06-01 00:00:00
abstract：:Several 4-alkyl-1-arylpiperazines that present a tetralin moiety on the terminal part of the side chain were synthesized in order to increase the selectivity on the 5-HT1A versus D-2, alpha 1, sigma, and other 5-HT receptors. Many changes have been effected on previous structures of type 3(1-aryl-4-[3-(1,2-dihydronaph...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00006a013
更新日期：1995-03-17 00:00:00
abstract：:The syntheses of three new cyclosporin A (CsA) analogues that contain novel MeBmt derivatives in the 1-position are described. The MeBmt analogue that contains an additional methyl group on C4, (2S,3R,6E)-4,4-dimethyl-3-hydroxy-2-(N-methylamino)-6-octenoic acid (MeBm2t), was synthesized in four steps beginning with th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00165a018
更新日期：1990-03-01 00:00:00
abstract：:Neuropeptide S (NPS) is the endogenous ligand of the previously orphan G-protein coupled receptor now named NPSR. The NPS-NPSR receptor system regulates important biological functions such as sleep/waking, locomotion, anxiety and food intake. Recently, exhaustive Ala scan and d-amino acid scan studies, together with s...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0706822
更新日期：2007-09-06 00:00:00
abstract：:The lack of molecules endowed with selective and potent agonistic activity toward the hA2B adenosine receptors has limited the studies on this pharmacological target and consequently the evaluation of its therapeutic potential. We report the design and the synthesis of the first potent (EC50 in the nanomolar range) an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm061170a
更新日期：2007-01-25 00:00:00
abstract：:A series of 3',5'-diesters of a 2,2'-anhydro-1-(beta-D-arabinofuranosyl)cytosine salt bearing functional substituents on the ester side chains (4--16) have been synthesized. The synthesis of these diesters involved the reaction between cytidine and the corresponding acid anhydride or acid chloride in the presence of b...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00192a007
更新日期：1979-06-01 00:00:00
abstract：:Activation of the IRE-1/XBP-1 pathway has been linked to many human diseases. We report a novel fluorescent tricyclic chromenone inhibitor, D-F07, in which we incorporated a 9-methoxy group onto the chromenone core to enhance its potency and masked the aldehyde to achieve long-term efficacy. Protection of the aldehyde...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b00269
更新日期：2019-06-13 00:00:00
abstract：:Novel lavendamycins including two water soluble derivatives were synthesized via short and efficient methods. Pictet-Spengler condensation of 7-N-acylamino-2-formylquinoline-5,8-diones with tryptophans produced lavendamycin esters or amides 11-17. Lavendamycins 18-21 were obtained, respectively, by further transformat...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0304414
更新日期：2003-12-18 00:00:00
abstract：:A series of trans-platinum(IV) complexes with functionalized aromatic carboxylate ligands, cis,cis,trans-Pt(NH3)2Cl2(CO2C6H4R)2 (R = H (3), p-vinyl (4), p-methoxy (5), p-iodo (6), p-cyano (7), or o-carboxyl (8)) was synthesized and characterized by spectroscopic methods. Crystal structures of 3, 4, 7, and 8 were obtai...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0506468
更新日期：2005-12-15 00:00:00
abstract：:On the basis of the initial success of optimization of a novel series of imidazolopiperazines, a second generation of compounds involving changes in the core piperazine ring was synthesized to improve antimalarial properties. These changes were carried out to further improve the potency and metabolic stability of the ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300041e
更新日期：2012-05-10 00:00:00
abstract：:Developing methods to incorporate protein flexibility into structure-based drug design is an important challenge. Our approach uses multiple protein structures (MPS) to create a receptor-based pharmacophore model of the desired target. We have previously demonstrated the success of the method by applying it to human i...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050755m
更新日期：2006-06-15 00:00:00
abstract：:Lofexidine, an alpha 2-agonist, has central hypotensive activity and peripheral intestinal antisecretory activity. Analogues were synthesized with increased polarity in an attempt to prevent penetration of the blood-brain barrier. The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00164a024
更新日期：1990-02-01 00:00:00
abstract：:The increasing prevalence of diabetes has accelerated the search for new drugs derived from natural sources. To define the functional features of two such families of compounds, the flavonols and the ethyl caffeates, we have determined the high-resolution structures of representative inhibitors in complex with human p...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm301273u
更新日期：2012-11-26 00:00:00
abstract：:Transient receptor potential canonical 3/6/7 (TRPC3/6/7) are highly homologous receptor-operated nonselective cation channels. Despite their physiological significance, very few selective and potent agonists are available for functional examination of these channels. Using a cell-based high throughput screening approa...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00304
更新日期：2017-06-08 00:00:00
abstract：:Dimeric DNA cross-linking compounds have emerged as important new antitumor agents. We report the synthesis and biochemical evaluation of a select set of dimeric mitomycins in which the two mitomycin units are tethered at either the mitomycin C(7) amino or the aziridine N(1a) positions. Significantly, mitomycin C (1) ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010090y
更新日期：2001-10-11 00:00:00
abstract：:In the past few years sirtuins have gained growing attention for their involvement in many biological processes such as cellular metabolism, apoptosis, aging and inflammation. In this contribution, we report the synthesis of a library of thioacetylated pseudopeptides that were screened against human sirtuins 1-3 to re...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400438k
更新日期：2013-09-12 00:00:00
abstract：:A series of analogues of the dipeptide sweetener L-aspartyl-L-phenylalanine methyl ester having hydroxy and/or methoxy substitution on the aromatic ring was synthesized and tasted. The introduction of a methoxy group in the para position of the aromatic ring of the peptide sweetener is crucial to the reduction or dest...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00178a013
更新日期：1980-04-01 00:00:00
abstract：:Type II beta-turn mimics and polyproline II helix mimics based upon diastereoisomeric 5.6.5 spiro bicyclic scaffolds have provided two pairs of Pro-Leu-Gly-NH(2) (PLG) peptidomimetics with contrasting dopamine receptor modulating activities. Compounds 1a and 3a were found to be positive allosteric modulators of the do...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801575w
更新日期：2009-04-09 00:00:00
abstract：:A series of 42 6-arylpyrrolo[2,1-d][1,5]benzothiazepines, which we have recently described as selective ligands of the mitochondrial benzodiazepine receptor (MBR) (Fiorini I.; et al. J. Med. Chem. 1994, 37, 1427-1438), have been investigated using the comparative molecular field analysis (CoMFA) approach. The resultin...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00050a007
更新日期：1994-11-25 00:00:00
abstract：:Enantiostructure-activity studies of chlorophenoxybutyric and propionic acids have provided evidence for the dissociation of serum cholesterol lowering and platelet antiaggregatory activities from the adverse chloride ion channel mediated myotonic effects of these compounds. R-(+) propionic and butyric acid enantiomer...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00391a001
更新日期：1987-08-01 00:00:00
abstract：:With a view to identify novel and biocompatible neuroprotectants, we designed nucleoside 5'-thiophosphate analogues, 6-11. We identified 2-SMe-ADP(α-S), 7A, as a most promising neuroprotectant. 7A reduced ROS production in PC12 cells under oxidizing conditions, IC50 of 0.08 vs 21 μM for ADP. Furthermore, 7A rescued pr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00575
更新日期：2015-11-12 00:00:00
abstract：:Fifteen anthracene-9,10-dione ("anthraquinone") derivatives with (omega-aminoalkyl)carboxamido substituents at the 1-, 2-, 1,4-, or 2, 6-ring positions were tested for bacterial mutagenicity in reverse-mutation assays using Salmonella typhimurium frameshift strains TA1538, TA98, and TA97a, in the presence and absence ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980167r
更新日期：1998-09-10 00:00:00
abstract：:We report compounds 5 (CG416) and 6 (CG428) as two first-in-class tropomyosin receptor kinase (TRK) degraders that target the intracellular kinase domain of TRK. Degraders 5 and 6 reduced levels of the tropomyosin 3 (TPM3)-TRKA fusion protein in KM12 colorectal carcinoma cells and inhibited downstream PLCγ1 signaling ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01342
更新日期：2020-12-10 00:00:00
abstract：:The problem of structure-activity relationships in sulfonamide type compounds is tackled on the ground that both bacteriostatic activities and structural indices must be referred to the specific individual forms assumed by sulfa drugs in the active solutions. The frequency value of the symmetric stretching mode of the...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00244a002
更新日期：1975-10-01 00:00:00
abstract：:A series of 8-phenylxanthine derivatives has been synthesized with oxyacetic acid on the para phenyl position to increase aqueous solubility and minimize nonspecific binding and iodinatable groups on the 1- or 3-position of the xanthine ring. The structure-activity relationship for binding of these compounds to A1 ade...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00399a010
更新日期：1988-04-01 00:00:00
abstract：:FK506-binding proteins (FKBPs) are evolutionarily conserved proteins that display peptidyl-prolyl isomerase activities and act as coreceptors for immunosuppressants. Microbial macrophage-infectivity-potentiator (Mip)-type FKBPs can enhance infectivity. However, developing druglike ligands for FKBPs or Mips has proven ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b00137
更新日期：2018-04-26 00:00:00
abstract：:Lysosomal enzymes are responsible for the degradation of a wide variety of glycolipids, oligosaccharides, proteins, and glycoproteins. Inherited mutations in the genes that encode these proteins can lead to reduced stability of newly synthesized lysosomal enzymes. While often catalytically competent, the mutated enzym...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/jm301557k
更新日期：2013-04-11 00:00:00
abstract：:The presence of lipopolysaccharide and emergence of drug resistance make the treatment of Gram-negative bacterial infections highly challenging. Herein, we present the synthesis and antibacterial activities of cholic acid-peptide conjugates (CAPs), demonstrating that valine-glycine dipeptide-derived CAP 3 is the most ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01357
更新日期：2019-02-28 00:00:00
