Pyrazole NNRTIs 3: Optimisation of physicochemical properties

Mowbray, Charles E.; Corbau, Romuald; Hawes, Michael; Jones, Lyn H.; Mills, James E.; Perros, Manos; Selby, Matthew D.; Stupple, Paul A.; Webster, Rob; Wood, Anthony

doi:10.1016/j.bmcl.2009.08.043

Cited by 29 publications

(26 citation statements)

References 4 publications

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“…The development of 33 from 82 (capravirine) provides an excellent case study in modulating ADME properties through nitrile substitution 93. Refining 82 led to the truncated analog 83 that was evaluated and found to be less potent and more lipophilic.…”

Section: Resultsmentioning

confidence: 99%

“…Structural optimization identified the nitrile and the corresponding chloride as being equipotent with the nitrile being much less lipophilic and more metabolically stable 93 . 34 (MIV-150) was developed as an NNRTI but is not suitable as an anti-viral therapy because of poor systemic absorption after oral administration 94.…”

Section: Arylnitrile-containing Pharmaceuticalsmentioning

confidence: 99%

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Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

et al. 2010

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Section: Resultsmentioning

confidence: 99%

Section: Arylnitrile-containing Pharmaceuticalsmentioning

confidence: 99%

Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

et al. 2010

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“…7a shows the snapshot of the overall superimposition of compound no. 47 and the virtually designed compounds (54)(55)(56)(57)(58)(59). 7b shows the a The compounds whose activity is reported in approximate terms.…”

Section: Validation Of Results For Vds By Docking and Virtual Screeningmentioning

confidence: 99%

“…55 Optimization of physicochemical properties, such as lipophilicity and increase ligand-lipophilicity efficiency (LLE) is reported by Mowbray et al 56 These descriptors are selected to characterize the molecular architecture for their capability to correlate diverse biochemical phenomena of the concerned molecular series. The four template groups incorporated in the present work are steric (S ALL ), hydrogen donor (HD ALL ), hydrogen acceptor (HA ALL ) and ring (R ALL ).…”

Section: Introductionmentioning

confidence: 99%

In silico de novo design of novel NNRTIs: a bio-molecular modelling approach

Jain¹,

Gupta

Sapre³

et al. 2015

RSC Adv.

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Six novel non-nucleoside reverse transcriptase inhibitors exhibiting high efficacy are designed using in silico mathematical modelling techniques and the results are validated using a docking technique. An in silico assessment of interaction potential and structural requirements of 5-alkyl-2-alkylamino-6-(2,6difluorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-one (DABO) analogues in the non-nucleoside inhibitor binding pocket is also performed. Efficient use of 3D-pharamacophoric (S ALL , HD ALL , HA ALL and R ALL ) and 3D-averaged alignment (C log P and dipole moment) descriptors is made in this study. The chemometric analyses, using support vector machine, back propagation neural network and multiple linear regression, are performed. The relative potentials of these chemometric methods is also assessed and the results,indicates that SVM describes the relationship between the descriptors and inhibitory activity in a better manner. The results also suggest that there is a non-linear relationship between the descriptors and inhibitory activity. The study further suggests that isopropyl/propenyl groups as R and R 0 , oxobutyl group as X and di or tri-substitution as R 00 are the best suited substituents for exhibiting better inhibitory activity.View Article Online a pEC 50 ¼ Àlog EC 50 (where EC 50 is the effective concentration of a compound required to activate 50% protection of MT-4 cell against the cytopathic effect of HIV-1). The data points a represent the test set and b as Outliers.This journal is

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“…奥普力农与甲状腺素运载蛋白的晶体复合物表明, 氰基吡啶酮部分位于荷尔蒙的结合口袋 [46] [47] . [49,50] . 将化合物 61 中的酰胺键去除, 得到化合物 62, 其逆转录酶的抑制活性减低 (IC 50 ＝ 0.56 μmol/L), 脂溶性增加(clog P＝4.0).…”

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Application of Nitrile in Drug Design

Wang¹,

Hong²

2012

Chin. J. Org. Chem.

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Nitrile-containing compounds comprise a substantial proportion in the therapeutic drugs. It is an important strategy to introduce nitrile substitute in the small molecule for structure-based medicinal chemistry. The application of nitrile in drug design is reviewed. The nitrile can modulate the physicochemical and pharmacokinetic properties to improve bioavailability, enhance the selectivities and binding affinity to target proteins by hydrogen bond interactions, covalent interactions, polar interactions, and π-π interactions. Meanwhile, the nitrile acts as bioisostere of various functional groups such as carbonyl and halogen groups. In addition, introducing the nitrile to drug molecules can block metabolically labile sites to increase the metabolic stability of drugs.

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Pyrazole NNRTIs 3: Optimisation of physicochemical properties

Cited by 29 publications

References 4 publications

Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

In silico de novo design of novel NNRTIs: a bio-molecular modelling approach

Application of Nitrile in Drug Design

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