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Introduction

DesignMedix is a pharmaceutical company that specializes in creating drugs to combat drug-resistant illnesses. Their current lineup includes RCQ anti-malaria drugs, modified acridone, and anti-bacterial drugs. With a focus on Oregon, they aim to cure malaria and address the growing issue of drug resistance in various diseases. Founded in 2006 by Sandra Lee Shotwell, David H. Peyton, and Lynnor B. Stevenson, the company is headquartered in Portland, OR.

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Infectious Diseases

Small molecule drug

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Disease Domain	Count

Infectious Diseases	1

Top 5 Drug Type	Count

Small molecule drug	1

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DNA	1

INTRODUCTIONThere is an urgent need to develop new drugs to treat malaria due to increasing resistance to first-line therapeutics targeting the causative organism, Plasmodium falciparum (P. falciparum). One drug candidate is DM1157, a small molecule that inhibits the formation of hemozoin, which protects P. falciparum from heme toxicity. We describe a first-in-human, phase 1 trial of DM1157 in healthy adult volunteers that was halted early because of significant toxicity.METHODSAdverse events were summarized using descriptive statistics. We used pharmacokinetic modeling to quantitatively assess whether the DM1157 exposure needed for P. falciparum inhibition was achievable at safe doses.RESULTSWe found that there was no dose where both the safety and efficacy target were simultaneously achieved; conversely, the model predicted that 27 mg was the highest dosage at which patients would consistently maintain safe exposure with multiple dosing. By pre-defining dose escalation stopping rules and conducting an interim pharmacokinetic/pharmacodynamic analysis, we determined that the study would be unable to safely achieve a dosage needed to observe an anti-malarial effect, thereby providing strong rationale to halt the study.CONCLUSIONThis study provides an important example of the risks and challenges of conducting early phase research as well as the role of modeling and simulation to optimize participant safety (ClinicalTrials.gov, NCT03490162).

01 May 2017·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Simplified Reversed Chloroquines To Overcome Malaria Resistance to Quinoline-Based Drugs

Q2 · MEDICINE

Article

Author: Gunsaru, Bornface ; Kelly, Jane X. ; Liebman, Katherine ; Shomloo, Shawheen ; Peyton, David H. ; Morrill, Westin ; Burgess, Steven J. ; Smilkstein, Martin J.

ABSTRACT Building on our earlier work of attaching a chemosensitizer (reversal agent) to a known drug pharmacophore, we have now expanded the structure-activity relationship study to include simplified versions of the chemosensitizer. The change from two aromatic rings in this head group to a single ring does not appear to detrimentally affect the antimalarial activity of the compounds. Data from in vitro heme binding and β -hematin inhibition assays suggest that the single aromatic RCQ compounds retain activities against Plasmodium falciparum similar to those of CQ, although other mechanisms of action may be relevant to their activities.

01 Sep 2015·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Contrasting Ex Vivo Efficacies of “Reversed Chloroquine” Compounds in Chloroquine-Resistant Plasmodium falciparum and P. vivax Isolates

Q2 · MEDICINE

Article

Author: Chalfein, Ferryanto ; Prayoga ; Noviyanti, Rintis ; Wirjanata, Grennady ; Sebayang, Boni F. ; Burgess, Steven J. ; Poespoprodjo, Jeanne Rini ; Price, Ric N. ; Handayuni, Irene ; Kenangalem, Enny ; Marfurt, Jutta ; Peyton, David H.

ABSTRACT Chloroquine (CQ) has been the mainstay of malaria treatment for more than 60 years. However, the emergence and spread of CQ resistance now restrict its use to only a few areas where malaria is endemic. The aim of the present study was to investigate whether a novel combination of a CQ-like moiety and an imipramine-like pharmacophore can reverse CQ resistance ex vivo . Between March to October 2011 and January to September 2013, two “reversed chloroquine” (RCQ) compounds (PL69 and PL106) were tested against multidrug-resistant field isolates of Plasmodium falciparum ( n = 41) and Plasmodium vivax ( n = 45) in Papua, Indonesia, using a modified ex vivo schizont maturation assay. The RCQ compounds showed high efficacy against both CQ-resistant P. falciparum and P. vivax field isolates. For P. falciparum , the median 50% inhibitory concentrations (IC 50 s) were 23.2 nM for PL69 and 26.6 nM for PL106, compared to 79.4 nM for unmodified CQ ( P < 0.001 and P = 0.036, respectively). The corresponding values for P. vivax were 19.0, 60.0, and 60.9 nM ( P < 0.001 and P = 0.018, respectively). There was a significant correlation between IC 50 s of CQ and PL69 (Spearman's rank correlation coefficient [ rs ] = 0.727, P < 0.001) and PL106 ( r s = 0.830, P < 0.001) in P. vivax but not in P. falciparum . Both RCQs were equally active against the ring and trophozoite stages of P. falciparum , but in P. vivax , PL69 and PL106 showed less potent activity against trophozoite stages (median IC 50 s, 130.2 and 172.5 nM) compared to ring stages (median IC 50 s, 17.6 and 91.3 nM). RCQ compounds have enhanced ex vivo activity against CQ-resistant clinical isolates of P. falciparum and P. vivax , suggesting the potential use of reversal agents in antimalarial drug development. Interspecies differences in RCQ compound activity may indicate differences in CQ pharmacokinetics between the two Plasmodium species.

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Pipeline

Pipeline Snapshot as of 27 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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