Structure-Activity Relationships of a Series of Echinocandins and the Discovery of CD101, a Highly Stable and Soluble Echinocandin with Distinctive 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.

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

Molecular Pharmacology ◽

10.1124/mol.108.053751 ◽

2009 ◽

Vol 76 (1) ◽

pp. 58-67 ◽

Cited By ~ 41

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

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Synergistic Lethality of a Binary Inhibitor ofMycobacterium tuberculosisKasA

mBio ◽

10.1128/mbio.02101-17 ◽

2018 ◽

Vol 9 (6) ◽

Cited By ~ 14

Author(s):

Pradeep Kumar ◽

Glenn C. Capodagli ◽

Divya Awasthi ◽

Riju Shrestha ◽

Karishma Maharaja ◽

...

Keyword(s):

Crystal Structure ◽

Cell Wall ◽

Mycobacterium Tuberculosis ◽

Substrate Binding ◽

Content Type ◽

X Ray ◽

Structure Activity Relationships ◽

Structure Activity ◽

Transcriptional Pattern

ABSTRACTWe report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) inMycobacterium tuberculosis. Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-Å resolution revealed two interacting DG167 molecules occupying nonidentical sites in the substrate-binding channel of KasA. The binding affinities of KasA to DG167 and its analog, 5g, which binds only once in the substrate-binding channel, were determined, along with the KasA-5g X-ray crystal structure. DG167 strongly augmented thein vitroactivity of isoniazid (INH), leading to synergistic lethality, and also synergized in an acute mouse model ofM. tuberculosisinfection. Synergistic lethality correlated with a unique transcriptional signature, including upregulation of oxidoreductases and downregulation of molecular chaperones. The lead structure-activity relationships (SAR), pharmacokinetic profile, and detailed interactions with the KasA protein that we describe may be applied to evolve a next-generation therapeutic strategy for tuberculosis (TB).IMPORTANCECell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors ofMycobacterium tuberculosisKasA—a key component for biosynthesis of the mycolic acid layer of the bacterium’s cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). One lead compound, DG167, demonstrated synergistic lethality in combination with INH and a transcriptional pattern consistent with bactericidality and loss of persisters. Our results also detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities. Together, these results suggest that KasA inhibition, specifically, that shown by the DG167 series, may be developed into a potent therapy that can synergize with existing antituberculars.

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Assessment of Inhibition of Bovine Hepatic Cytochrome P450 by 43 Commercial Bovine Medicines Using a Combination of In Vitro Assays and Pharmacokinetic Data from the Literature

Drug Metabolism Letters ◽

10.2174/1872312813666191120094649 ◽

2020 ◽

Vol 13 (2) ◽

pp. 123-131

Author(s):

Steven X. Hu ◽

Chase A. Mazur ◽

Kenneth L. Feenstra

Keyword(s):

Liver Microsomes ◽

In Vitro Assay ◽

In Vitro Assays ◽

Pharmacokinetic Studies ◽

Pharmacokinetic Data ◽

Vitro Assay ◽

Administration Routes ◽

Ic50 Values

Background: There has been a lack of information about the inhibition of bovine medicines on bovine hepatic CYP450 at their commercial doses and dosing routes. Objective: The aim of this work was to assess the inhibition of 43 bovine medicines on bovine hepatic CYP450 using a combination of in vitro assay and Cmax values from pharmacokinetic studies with their commercial doses and dosing routes in the literature. Methods: Those drugs were first evaluated through a single point inhibitory assay at 3 μM in bovine liver microsomes for six specific CYP450 metabolisms, phenacetin o-deethylation, coumarin 7- hydroxylation, tolbutamide 4-hydroxylation, bufuralol 1-hydroxylation, chlorzoxazone 6-hydroxylation and midazolam 1’-hydroxylation. When the inhibition was greater than 20% in the assay, IC50 values were then determined. The potential in vivo bovine hepatic CYP450 inhibition by those drugs was assessed using a combination of the IC50 values and in vivo Cmax values from pharmacokinetic studies at their commercial doses and administration routes in the literature. Results: Fifteen bovine medicines or metabolites showed in vitro inhibition on one or more bovine hepatic CYP450 metabolisms with different IC50 values. Desfuroylceftiour (active metabolite of ceftiofur), nitroxinil and flunixin have the potential to inhibit one of the bovine hepatic CYP450 isoforms in vivo at their commercial doses and administration routes. The rest of the bovine medicines had low risks of in vivo bovine hepatic CYP450 inhibition. Conclusion: This combination of in vitro assay and in vivo Cmax data provides a good approach to assess the inhibition of bovine medicines on bovine hepatic CYP450.

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Enantiomers of Nifurtimox Do Not Exhibit Stereoselective Anti-Trypanosoma cruzi Activity, Toxicity, or Pharmacokinetic Properties

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05139-14 ◽

2015 ◽

Vol 59 (6) ◽

pp. 3645-3647 ◽

Cited By ~ 1

Author(s):

Carolina B. Moraes ◽

Karen L. White ◽

Stéphanie Braillard ◽

Catherine Perez ◽

Junghyun Goo ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

Murine Model ◽

Therapeutic Benefit ◽

Racemic Mixture ◽

Content Type ◽

Pharmacokinetic Properties

ABSTRACTWith the aim of improving the available drugs for the treatment of Chagas disease, individual enantiomers of nifurtimox were characterized. The results indicate that the enantiomers are equivalent in theirin vitroactivity against a panel ofTrypanosoma cruzistrains;in vivoefficacy in a murine model of Chagas disease;in vitrotoxicity and absorption, distribution, metabolism, and excretion characteristics; andin vivopharmacokinetic properties. There is unlikely to be any therapeutic benefit of an individual nifurtimox enantiomer over the racemic mixture.

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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

Bioconjugate Chemistry ◽

10.1021/bc010098m ◽

2002 ◽

Vol 13 (4) ◽

pp. 773-785 ◽

Cited By ~ 69

Author(s):

Katja Riebeseel ◽

Elfi Biedermann ◽

Roland Löser ◽

Norbert Breiter ◽

Ralf Hanselmann ◽

...

Keyword(s):

Molecular Weight ◽

Polyethylene Glycol ◽

Structure Activity Relationships ◽

Structure Activity

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Conjugated Dienes as Prohaptens in Contact Allergy: In Vivo and in Vitro Studies of Structure−Activity Relationships, Sensitizing Capacity, and Metabolic Activation

Chemical Research in Toxicology ◽

10.1021/tx060006n ◽

2006 ◽

Vol 19 (6) ◽

pp. 760-769 ◽

Cited By ~ 37

Author(s):

Moa Andresen Bergström ◽

Kristina Luthman ◽

J. Lars G. Nilsson ◽

Ann-Therese Karlberg

Keyword(s):

Contact Allergy ◽

Metabolic Activation ◽

Conjugated Dienes ◽

In Vitro Studies ◽

Structure Activity Relationships ◽

Structure Activity

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00386-06 ◽

2006 ◽

Vol 50 (10) ◽

pp. 3435-3443 ◽

Cited By ~ 9

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.

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High Accumulation and In Vivo Recycling of the New Antimalarial Albitiazolium Lead to Rapid Parasite Death

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00352-17 ◽

2017 ◽

Vol 61 (8) ◽

Cited By ~ 4

Author(s):

Sharon Wein ◽

Nicolas Taudon ◽

Marjorie Maynadier ◽

Christophe Tran Van Ba ◽

Delphine Margout ◽

...

Keyword(s):

Pharmacological Activity ◽

Plasma Concentrations ◽

Pharmacokinetic Studies ◽

High Accumulation ◽

Content Type ◽

Viability Assay ◽

Parasite Viability ◽

Two Parameters

ABSTRACT Albitiazolium is the lead compound of bisthiazolium choline analogues and exerts powerful in vitro and in vivo antimalarial activities. Here we provide new insight into the fate of albitiazolium in vivo in mice and how it exerts its pharmacological activity. We show that the drug exhibits rapid and potent activity and has very favorable pharmacokinetic and pharmacodynamic properties. Pharmacokinetic studies in Plasmodium vinckei-infected mice indicated that albitiazolium rapidly and specifically accumulates to a great extent (cellular accumulation ratio, >150) in infected erythrocytes. Unexpectedly, plasma concentrations and the area under concentration-time curves increased by 15% and 69% when mice were infected at 0.9% and 8.9% parasitemia, respectively. Albitiazolium that had accumulated in infected erythrocytes and in the spleen was released into the plasma, where it was then available for another round of pharmacological activity. This recycling of the accumulated drug, after the rupture of the infected erythrocytes, likely extends its pharmacological effect. We also established a new viability assay in the P. vinckei-infected mouse model to discriminate between fast- and slow-acting antimalarials. We found that albitiazolium impaired parasite viability in less than 6 and 3 h at the ring and late stages, respectively, while parasite morphology was affected more belatedly. This highlights that viability and morphology are two parameters that can be differentially affected by a drug treatment, an element that should be taken into account when screening new antimalarial drugs.

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