Polyethylene Glycol Conjugates of Methotrexate Varying in Their Molecular Weight from MW 750 to MW 40000:  Synthesis, Characterization, and Structure−Activity Relationships in Vitro and in Vivo

2002 ◽  
Vol 13 (4) ◽  
pp. 773-785 ◽  
Author(s):  
Katja Riebeseel ◽  
Elfi Biedermann ◽  
Roland Löser ◽  
Norbert Breiter ◽  
Ralf Hanselmann ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Polyethylene Glycol ◽  
Structure Activity Relationships ◽  
Structure Activity

In Vivo and in Vitro Structure-Activity Relationships and Structural Conformation of Kisspeptin-10-Related Peptides

2009 ◽  
Vol 76 (1) ◽  
pp. 58-67 ◽  
Author(s):  
Ester Gutiérrez-Pascual ◽  
Jérôme Leprince ◽  
Antonio J. Martínez-Fuentes ◽  
Isabelle Ségalas-Milazzo ◽  
Rafael Pineda ◽  
...  
Keyword(s):  
Structure Activity Relationships ◽  
Structural Conformation ◽  
Structure Activity

scholarly journals Structure-Activity Relationships of a Series of Echinocandins and the Discovery of CD101, a Highly Stable and Soluble Echinocandin with Distinctive Pharmacokinetic Properties

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Kenneth D. James ◽  
Christopher P. Laudeman ◽  
Navdeep B. Malkar ◽  
Radha Krishnan ◽  
Karen Polowy
Keyword(s):  
Pharmacokinetic Studies ◽  
Pharmacokinetic Data ◽  
Activity Data ◽  
Content Type ◽  
Structure Activity Relationships ◽  
First Line Therapy ◽  
Structure Activity ◽  
Pharmacokinetic Properties

ABSTRACT Echinocandins are a first-line therapy for candidemia and invasive candidiasis. They are generally safe with few drug interactions, but the stability and pharmacokinetic properties of currently approved echinocandins are such that each was developed for daily intravenous infusion. We sought to discover a novel echinocandin with properties that would enable more flexible dosing regimens, alternate routes of delivery, and expanded utility. Derivatives of known echinocandin scaffolds were generated, and an iterative process of design and screening led to the discovery of CD101, a novel echinocandin that has since demonstrated improved chemical stability and pharmacokinetics. Here, we report the structure-activity relationships (including preclinical efficacy and pharmacokinetic data) for the series of echinocandin analogs from which CD101 was selected. In a mouse model of disseminated candidiasis, the test compounds displayed clear dose responses and were generally associated with lower fungal burdens than that of anidulafungin. Single-dose pharmacokinetic studies in beagle dogs revealed a wide disparity in the half-lives and volumes of distribution, with one compound (now known as CD101) displaying a half-life that is nearly 5-fold longer than that of anidulafungin (53.1 h versus 11.6 h, respectively). In vitro activity data against panels of Candida spp. and Aspergillus spp. demonstrated that CD101 behaved similarly to approved echinocandins in terms of potency and spectrum of activity, suggesting that the improved efficacy observed in vivo for CD101 is a result of features beyond the antifungal potency inherent to the molecule. Factors that potentially contribute to the improved in vivo efficacy of CD101 are discussed.

scholarly journals Structure-Activity Relationships of Bacillus cereus and Bacillus anthracis Dihydrofolate Reductase: toward the Identification of New Potent Drug Leads

2006 ◽  
Vol 50 (10) ◽  
pp. 3435-3443 ◽  
Author(s):  
Tammy M. Joska ◽  
Amy C. Anderson
Keyword(s):  
Bacillus Cereus ◽  
Bacillus Anthracis ◽  
Dihydrofolate Reductase ◽  
Antimicrobial Agents ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Phenyl Rings ◽  
Potent Drug

ABSTRACT New and improved therapeutics are needed for Bacillus anthracis, the etiological agent of anthrax. To date, antimicrobial agents have not been developed against the well-validated target dihydrofolate reductase (DHFR). In order to address whether DHFR inhibitors could have potential use as clinical agents against Bacillus, 27 compounds were screened against this enzyme from Bacillus cereus, which is identical to the enzyme from B. anthracis at the active site. Several 2,4-diamino-5-deazapteridine compounds exhibit submicromolar 50% inhibitory concentrations (IC50s). Four of the inhibitors displaying potency in vitro were tested in vivo and showed a marked growth inhibition of B. cereus; the most potent of these has MIC50 and minimum bactericidal concentrations at which 50% are killed of 1.6 μg/ml and 0.09 μg/ml, respectively. In order to illustrate structure-activity relationships for the classes of inhibitors tested, each of the 27 inhibitors was docked into homology models of the B. cereus and B. anthracis DHFR proteins, allowing the development of a rationale for the inhibition profiles. A combination of favorable interactions with the diaminopyrimidine and substituted phenyl rings explains the low IC50 values of potent inhibitors; steric interactions explain higher IC50 values. These experiments show that DHFR is a reasonable antimicrobial target for Bacillus anthracis and that there is a class of inhibitors that possess sufficient potency and antibacterial activity to suggest further development.

In vitro–in vivo antifungal evaluation and structure–activity relationships of 3H-1,2-dithiole-3-thione derivatives

Il Farmaco ◽  
2004 ◽  
Vol 59 (4) ◽  
pp. 245-254 ◽  
Author(s):  
Fernando A Giannini ◽  
Mario L Aimar ◽  
Maximiliano Sortino ◽  
Roxana Gomez ◽  
Alejandro Sturniollo ◽  
...  
Keyword(s):  
Structure Activity Relationships ◽  
Structure Activity

Induction of peroxisomal β-oxidation in the rat liver in vivo and in vitro by tetrazole-substituted acetophenones: Structure-activity relationships

1989 ◽  
Vol 100 (1) ◽  
pp. 177-184 ◽  
Author(s):  
P.I. Eacho ◽  
P.S. Foxworthy ◽  
R.D. Dillard ◽  
C.A. Whitesitt ◽  
D.K. Herron ◽  
...  
Keyword(s):  
Rat Liver ◽  
Structure Activity Relationships ◽  
Structure Activity
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