Journal of Medicinal Chemistry
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An Effective Prodrug Strategy to Selectively Enhance Ocular Exposure of a Cannabinoid Receptor (CB1/2) Agonist.
We present an innovative strategy to rapidly identify compound A prodrugs that are efficiently metabolized to the parent compound, for improved solubility and ocular permeability, while maintaining low systemic exposures....
Novel β-amino acid derivatives as inhibitors of cathepsin A.
We identified novel β-amino acid derivatives as inhibitors of CatA after a HTS analysis based on a project adapted fragment approach. The new inhibitors showed beneficial ADME and pharmacokinetic profiles, and their binding modes were established by X-ray crystallography. Further investigations led...
A new class of selective and potent 7-dehydrocholesterol reductase inhibitors.
We prepared a number of N-phenethyltetrahydroisoquinolines structurally related to protoberberines. They were tested for activity against bacteria, fungi and human leukaemia HL-60 cells and also for inhibition of biosynthesis: ergosterol in yeasts and cholesterol in human cells. In the latter assay...
Design, synthesis, and pharmacological evaluation of novel hybrid compounds to treat sickle cell disease symptoms. part II: furoxan derivati...
Phthalimide derivatives containing furoxanyl subunits as nitric oxide (NO)-donors (3a-g) were designed, synthesized, and evaluated in vitro and in vivo for their potential uses in the oral treatment of sickle cell disease symptoms. All compounds (3a-g) demonstrated NO-donor propertie...
Rational design of a low molecular weight, stable, potent, and long-lasting GPR103 aza-β3-pseudopeptide agonist.
We have designed a series of aza-β3-containing 26RFa(20-26) analogs for their propensity to establish intramolecular hydrogen bonds, and we have evaluated their ability to increase [Ca2+]i in GPR103-transfected cells. We have identified a compound, [Cmpi21,aza-β3-Hht23]26RFa(21-26), which was 8-fo...
Factors influencing the specificity of inhibitor binding to the human and malaria parasite dihydroorotate dehydrogenases.
The de novo pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase is an emerging drug target for the treatment of malaria. In this context a key property of Plasmodium falciparum DHODH (PfDHODH) is that it can be selectively inhibited over its human homologue (HsDHODH). However...
Azapeptide analogues of the growth hormone releasing peptide 6 as cluster of differentiation 36 receptor ligands with reduced affinity for t...
The synthetic hexapeptide Growth Hormone Releasing Peptide-6 (GHRP-6) exhibits dual affinity for the Growth Hormone Secretagogue Receptor 1a (GHS-R1a) and the Cluster of Differentiation 36 (CD36) receptor. Azapeptide GHRP-6 analogs have been synthesized exhibiting micromolar affinity...
Human neutrophil elastase phosphonic inhibitors with improved potency of action.
We present the synthesis and the measurement of the inhibitory activity of novel peptidyl derivatives of α-aminoalkylphosphonate diaryl esters as human neutrophil elastase inhibitors. Their selectivity against other serine proteases, including porcine pancreatic elastase, chymotrypsin and trypsin,...
Design, synthesis, and pharmacological evaluation of glutamate carboxypeptidase II (GCPII) inhibitors based on thioalkylbenzoic acid scaffol...
A series of thiol-based glutamate carboxypeptidase II (GCPII) inhibitors have been synthesized with either a 3-(mercaptomethyl)benzoic acid or 2-(2-mercaptoethyl)benzoic acid scaffold. Potent inhibitors were identified from each of the two scaffolds with IC(50) values in the single-d...
Nonhematotoxic naphthalene diimide modified by polyamine: synthesis and biological evaluation.
With the aim of up-regulating antitumor efficacy and down-regulating adverse effects, three types of aromatic imide and diimides were designed to couple with different polyamines. The in vitro assays revealed that two naphthalene diimide-polyamine conjugates could inhibit the growth of multiple cance...