Structure–Activity Relationships of 4-Position Diamine Quinoline Methanols as Intermittent Preventative Treatment (IPT) against <i>Plasmodium falciparum</i>

Milner, Erin; Gardner, Sean; Moon, Jay; Grauer, Kristina; Auschwitz, Jennifer M.; Bathurst, Ian C.; Caridha, Diana; Gerena, Lucia; Gettayacamin, Montip; Johnson, Jacob; Kozar, Michael P.; Lee, Patricia; Leed, Susan E.; Li, Qigui; McCalmont, William; Meléndez, Víctor; Roncal, Norma; Sciotti, Richard J.; Smith, Bryan; Sousa, Jason; Tungtaeng, Anchalee; Wipf, Peter; Dow, Geoffrey S.

doi:10.1021/jm200647u

Cited by 22 publications

(7 citation statements)

References 11 publications

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“…A set of 92 compounds was collected from ChEMBL, − with the aim of finding three series of related analogues for which MDCK permeability data were available. Molecules in this data set were not synthesized at Genentech.…”

Section: Methodsmentioning

confidence: 99%

Predicting Passive Permeability of Drug-like Molecules from Chemical Structure: Where Are We?

Broccatelli¹,

Salphati²,

Plise³

et al. 2016

Mol. Pharmaceutics

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Intestinal absorption in human is routinely predicted in drug discovery using in vitro assays such as permeability in the Madin-Darby canine kidney cell line. In silico models trained on these data are used in drug discovery efforts to prioritize novel chemical targets for synthesis; however, their proprietary nature and the limited validation available, which is usually restricted to predicting in vitro permeability, are barriers to widespread adoption. Because of the categorical nature of the in vitro permeability assay, intrinsic assay variability, and the challenges often encountered when translating in vitro data to an in vivo drug property, validation based solely on in vitro data might not be a good characterization of the usefulness of the in silico tool. In this work, we analyze the performance of three different in silico models in predicting the in vitro and in vivo permeability of 300 marketed drugs and 86 discovery compounds. The models differ in their approach (mechanistic vs quantitative structure-activity relationship) and the degree of complexity; one of them is a linear equation based on seven simple physicochemical descriptors and is presented for the first time in this work. Results show that in silico models can be successfully used to complement the discovery toolbox for characterizing in vivo intestinal permeability, defined using fraction of dose absorbed in human (Fa) and human jejunal permeability (P). While the in vitro permeability models outperformed the in silico approach at predicting each of the in vivo end points explored, the gap in predictivity between the in vitro and the in vivo data was generally comparable to the gap between in silico and in vitro data. The in vitro and in silico approaches shared many of the same outliers, which can often be explained by the route of drug absorption (paracellular vs transcellular, active vs passive). Data suggest that the discovery process can greatly benefit from an early adoption of in silico models for predicting permeability as well as from a careful analysis of the in silico to in vivo disconnects.

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Section: Methodsmentioning

confidence: 99%

Predicting Passive Permeability of Drug-like Molecules from Chemical Structure: Where Are We?

Broccatelli¹,

Salphati²,

Plise³

et al. 2016

Mol. Pharmaceutics

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“…Walter Reed Army Institute of Research screened for analogs with a lower brain penetration, and have identified WR621308, which has a substantially lower permeability across MDCK cell monolayers than mefloquine, suggesting lower brain exposures [9].…”

Section: Discussionmentioning

confidence: 99%

Antimalaria Drug Development & Pipeline

Lahiry¹,

eep²,

Sinha³

2017

JAPLR

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Increasing incidence of artemisin resistance endangers very foundations of current guideline based antimalarial therapy. There is an unmet need to develop newer strategies, targeting novel pathophysiology to set high standards in antimalaria care. Of late, the antimalarial drug pipeline is becoming increasingly robust, and promises healthier outcomes. We discuss few drugs currently under pre-clinical development that have shown encouraging results.

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“…Very recently, Milner et al have utilised microwave-assisted nucleophilic epoxide ring opening reactions to prepare a library of diamine quinoline methanol derivatives, based on the mefloquine (MQ) scaffold (Scheme 26). 124 The most promising candidate 57 was prepared by reacting the enantiopure epoxide 55 with amine 56 under microwave conditions, followed by an acid mediated deprotection of the Boc group. Compound 57 exhibited similar potency to MQ across a range of drug resistant Pf strains and after single dose administration in mice, cured 4 out of 126 Gilbert and co-workers have reported the discovery of acyclic uracil-based inhibitors of the Pf enzyme deoxyuridine nucleotidohydrolyase (dUTPase).…”

Section: Malariamentioning

confidence: 99%

Microwave-assisted synthesis of small molecules targeting the infectious diseases tuberculosis, HIV/AIDS, malaria and hepatitis C

2012

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The unique properties of microwave in situ heating offer unparalleled opportunities for medicinal chemists to speed up lead optimisation processes in early drug discovery. The technology is ideal for small-scale discovery chemistry because it allows full reaction control, short reaction times, high safety and rapid feedback. To illustrate these advantages, we herein describe applications and approaches in the synthesis of small molecules to combat four of the most prevalent infectious diseases; tuberculosis, HIV/AIDS, malaria and hepatitis C, using dedicated microwave instrumentation.

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Structure–Activity Relationships of 4-Position Diamine Quinoline Methanols as Intermittent Preventative Treatment (IPT) against Plasmodium falciparum

Cited by 22 publications

References 11 publications

Predicting Passive Permeability of Drug-like Molecules from Chemical Structure: Where Are We?

Predicting Passive Permeability of Drug-like Molecules from Chemical Structure: Where Are We?

Antimalaria Drug Development & Pipeline

Microwave-assisted synthesis of small molecules targeting the infectious diseases tuberculosis, HIV/AIDS, malaria and hepatitis C

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