Abstract：
:The efficacious dose of a drug is perhaps the most holistic metric reflecting its therapeutic potential. Dose is predicted at many stages in drug discovery and development. Prior to the 1990s, dose prediction was limited to the drug "working" at a reasonable dose and dose regimen in an animal model. Through the early 2000s, dose predictions were generated at candidate nomination and then refined during clinical development. Currently, dose predictions can be made early in drug discovery to enable drug design. Dose predictions at this stage can identify critical drug properties for a viable dose regimen and provide clinically relevant context to lead optimization. In this paper, we give an overview of the opportunities and challenges associated with dose prediction for drug design. A number of general considerations, approaches, and case examples are discussed.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Maurer TS,Smith D,Beaumont K,Di Ldoi
10.1021/acs.jmedchem.9b01365subject
Has Abstractpub_date
2020-06-25 00:00:00pages
6423-6435issue
12eissn
0022-2623issn
1520-4804journal_volume
63pub_type
杂志文章abstract：:Quadruplex-forming sequences are widely prevalent in human and other genomes, including bacterial ones. These sequences are over-represented in eukaryotic telomeres, promoters, and 5' untranslated regions. They can form quadruplex structures, which may be transient in many situations in normal cells since they can be ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01835
更新日期：2016-07-14 00:00:00
abstract：:A variety of nitroheterocyclic carbamate prodrugs of phenylenediamine mustard and 5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-benz[e]indoline (amino-seco-CBI-TMI), covering a wide range of reduction potential, were prepared and evaluated for use in gene-directed enzyme prodrug ther...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030308b
更新日期：2003-12-04 00:00:00
abstract：:Four chiral congeners of arachidonylethanolamide (anandamide) have been synthesized and evaluated for (a) their ability to bind to the cannabinoid receptor in rat forebrain membranes and (b) their pharmacological potency as measured by the compounds' ability to inhibit electrically-evoked contractions of the mouse vas...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00038a020
更新日期：1994-06-10 00:00:00
abstract：:A series of 6,9-disubstituted purines were tested for their ability to bind to the benzodiazepine receptor in rat brain tissue. One of the most active compounds was 9-(3-aminobenzyl)-6-(dimethylamino)-9H-purine (44) with an IC50 = 0.9 microM, which was only 4.5-fold higher than the IC50 for chlordiazepoxide. Substitut...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00125a015
更新日期：1989-05-01 00:00:00
abstract：:Homology modeling of G-protein-coupled seven-transmembrane receptors (GPCRs) remains a challenge despite the increasing number of released GPCR crystal structures. This challenge can be attributed to the low sequence identity and structural diversity of the ligand-binding pocket of GPCRs. We have developed an optimize...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400307y
更新日期：2013-06-13 00:00:00
abstract：:New efficient antifungal agents are urgently needed to treat drug-resistant fungal infections. Here, we designed and synthesized a series of cationic xanthone amphiphilics as antifungal agents from natural α-mangostin to combat fungal resistance. The attachment of cationic residues on the xanthone scaffold of α-mangos...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01348
更新日期：2017-12-28 00:00:00
abstract：:The atypical chemokine receptor 3 (ACKR3)/CXC chemokine receptor 7 (CXCR7) recognizes stromal cell-derived factor 1 (SDF-1)/CXCL12 and is involved in a number of physiological and pathological processes. Here, we investigated the SAR of the component amino acids in an ACKR3-selective ligand, FC313 [ cyclo(-d-Tyr-l-Arg...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b00336
更新日期：2018-04-26 00:00:00
abstract：:A number of 7-benzoylbenzofuran-5-ylacetic acids and 7-benzoylbenzothiophene-5-ylacetic acids were synthesized. The compounds were generally only 1/2 to 3 times as potent as phenylbutazone in the rat paw edema antiinflammatory assay. However, they show greater activity as analgetic agents. The most active compound is ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00161a030
更新日期：1986-11-01 00:00:00
abstract：:Androgen receptors are present in most advanced prostate cancer specimens, having a critical role in development of this type of cancer. For correct prognosis of patient conditions and treatment monitoring, noninvasive imaging techniques have great advantages over surgical procedures. We developed synthetic methodolog...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100289b
更新日期：2010-09-09 00:00:00
abstract：:Using reported glutathione S-transferase omega 1 (GSTO1-1) cocrystal structures, we designed and synthesized acrylamide-containing compounds that covalently bind to Cys32 on the catalytic site. Starting from a thiazole derivative 10 (GSTO1-1 IC50 = 0.6 μM), compound 18 was synthesized and cocrystallized with GSTO1. Mo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01960
更新日期：2019-03-28 00:00:00
abstract：:A series of amino acids, amidino acids, and amidino esters was synthesized and the compounds were evaluated for their inhibitory activity against bovine trypsin, bovine thrombin, and porcine pancreatic kallikrein and as anticoagulants. Among these compounds, ethyl 4-amidino-2-iodophenoxyacetate was found to be the mos...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00237a016
更新日期：1975-03-01 00:00:00
abstract：:Forty-eight heterocyclic amino acid trimers, analogues of distamycin, with a number of features that enhance lipophilicity are described. They contain alkyl or cycloalkyl groups larger than methyl; some are N-terminated by acetamide or methoxybenzamide and are C-terminated by dimethylaminopropyl or aliphatic heterocyl...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm031089x
更新日期：2004-04-08 00:00:00
abstract：:A series of eight C5-substituted analogues of (+-)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (1) have been prepared by the directed lithiation-alkylation (and acylation) of its (+-)-N-tert-butylformamidinyl derivative 2 followed by formamidine solvolysis. An additional 10 analogues were prepared by elaborati...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00165a029
更新日期：1990-03-01 00:00:00
abstract：:In this study we present the synthesis and some pharmacological properties of nine new analogues of arginine vasopressin modified in the N-terminal part of the molecule with 2-aminoindane-2-carboxylic acid (Aic). The peptides were tested for their in vitro uterotonic and in vivo pressor and antidiuretic activities. On...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070174s
更新日期：2007-06-14 00:00:00
abstract：:N-(5,5-Diacetoxypent-1-yl)doxorubicin (1b) is an intensely cytotoxic doxorubicin analogue that retains full potency against tumor cells that express elevated levels of P-glycoprotein and are resistant to doxorubicin. 1b was designed to be hydrolyzed in the presence of carboxylate esterases to N-(5-oxypent-1-yl)doxorub...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9706980
更新日期：1998-03-12 00:00:00
abstract：:Increased usage of daptomycin to treat infections caused by Gram-positive bacterial pathogens has resulted in emergence of resistant mutants. In a search for more effective daptomycin analogues through medicinal chemistry studies, we found that methylation at the nonproteinogenic amino acid kynurenine in daptomycin co...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01957
更新日期：2020-03-26 00:00:00
abstract：:(4-Methoyx-2,3,6-trimethylphenyl)nonatetraenoic acids, esters, and amides (analogues of retinoic acid) bearing a fluorine atom(s) or a trifluoromethyl group on the polyene side chain were synthesized. The biological activities of these compounds and of 10-, 12-, and 14-fluororetinoic acid esters were evaluated in vivo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00195a010
更新日期：1979-09-01 00:00:00
abstract：:Structure-based strategy was employed to design flavonoid compounds to mimic the Bim BH3 peptide as a new class of inhibitors of the anti-apoptotic Bcl-2 proteins. The most potent compound, 4 (BI-33), binds to Bcl-2 and Mcl-1 with Ki values of 17 and 18 nM, respectively. Compound 4 inhibits cell growth in the MDA-MB-2...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070383c
更新日期：2007-07-12 00:00:00
abstract：:A series of novel tacrine derivatives and tacrine-coumarin heterodimers were designed, synthesized, and biologically evaluated for their potential inhibitory effect on both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Of these compounds, tacrine-coumarin heterodimer 7c and tacrine derivative 6b were ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm5008648
更新日期：2014-08-28 00:00:00
abstract：:Previous SAR studies (Part 1: Mai, A.; et al. J. Med. Chem. 2003, 46, 512-524) performed on some portions (pyrrole-C4, pyrrole-N1, and hydroxamate group) of 3-(4-benzoyl-1-methyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamide (1a) highlighted its 4-phenylacetyl (1b) and 4-cynnamoyl (1c) analogues as more potent compounds in ...
journal_title：Journal of medicinal chemistry
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doi：10.1021/jm030990+
更新日期：2004-02-26 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
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更新日期：2014-11-26 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b01586
更新日期：2017-04-13 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：:We describe here a classical molecular modeling exercise that was carried out to provide a basis for the design of novel antagonist ligands of the CCR2 receptor. Using a theoretical model of the CCR2 receptor, docking studies were carried out to define plausible binding modes for the various known antagonist ligands, ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030862l
更新日期：2003-09-11 00:00:00
abstract：:A series of 2-aryl-4-benzoyl-imidazoles (ABI) was synthesized as a result of structural modifications based on the previous set of 2-aryl-imidazole-4-carboxylic amide (AICA) derivatives and 4-substituted methoxylbenzoyl-aryl-thiazoles (SMART). The average IC(50) of the most active compound (5da) was 15.7 nM. ABI analo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100884b
更新日期：2010-10-28 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00171a024
更新日期：1990-09-01 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01249
更新日期：2016-01-14 00:00:00
abstract：:The binding affinities at rat A1, A2a, and A3 adenosine receptors of a wide range of derivatives of adenosine have been determined. Sites of modification include the purine moiety (1-, 3-, and 7-deaza; halo, alkyne, and amino substitutions at the 2- and 8-positions; and N6-CH2-ring, -hydrazino, and -hydroxylamino) and...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00007a014
更新日期：1995-03-31 00:00:00
abstract：:A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of β-adrenergic signaling in vitro studies. Hydrazone derivative 5 and 1,2,4-triazole derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00443
更新日期：2017-08-24 00:00:00
abstract：:Previous quantitative and qualitative structure-activity studies in antibacterial monosubstituted 1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids prompted us to synthesize the 6,7,8-polysubstituted compounds. In this paper, the preparation and antibacterial activity of the 6,7- and 7,8-disubstituted compounds an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00186a014
更新日期：1980-12-01 00:00:00
