Design principles for orally bioavailable drugs

Navia, Manuel A.; Chaturvedi, Pravin

doi:10.1016/1359-6446(96)10020-9

Cited by 193 publications

(130 citation statements)

References 48 publications

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“…In addition to the physicochemical parameters described by Lipinski et al, [18] other properties [19,20] have been related to oral bioavailability. Among them, decreased molecular flexibility (which may be related to the number of rotatable bonds) has been reported as an important predictor for good oral bioavailability, independent of molecular weight.…”

Section: Discussionmentioning

confidence: 98%

“…[17] Unfortunately, this remains too weak to envisage further clinical development. Examination of some molecular parameters [18][19][20] (such as molecular weight, flexibility as determined by the number of rotatable bounds, and lipophilicity) of the prodrugs of T3 revealed that they are unsuitable for oral administration. To modulate molecular flexibility, a parameter common to both the drug and its corresponding prodrug, we envisaged a new series of T3 analogues in which the linker (dodecyl chain) is rigidified through the introduction of an aromatic moiety ( Figure 2).…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Evaluation of Bis‐Thiazolium Salts as Potential Antimalarial Drugs

et al. 2010

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An innovative therapeutic approach based on the use of dicationic derivatives was previously designed to inhibit the biosynthesis of phosphatidylcholine in Plasmodium spp. Among these, bis-thiazolium salts were shown to block proliferation of the malaria parasite at concentrations in the low nanomolar range. However, due to unsuitable molecular properties such as the presence of the two polar heads and flexibility in the linker, these compounds have low oral bioavailability. To characterize the structural requirements of the linker that lead to more rigid analogues with fewer rotatable bonds but which retain antimalarial activity, a new series of compounds incorporating an aryl moiety and eventually oxygen atoms were prepared, and their biological activity was evaluated. Structure-activity relationships suggest that the optimal linker construct is an aromatic group with two n-butyl chains branched at the para position; two new leads (compounds 39 and 40) were selected for further development.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Bis‐Thiazolium Salts as Potential Antimalarial Drugs

et al. 2010

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“…Potent ligands were developed but not drugs. [52] Further development of the compounds found was discontinued owing to variable bioavailability and/ or excessive production costs. Availability of detailed structural information had not aided the rational design of potent inhibitors with an acceptable pharmacokinetic profile.…”

Section: Reviewsmentioning

confidence: 99%

Application and Limitations of X‐ray Crystallographic Data in Structure‐Based Ligand and Drug Design

2003

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Structure-based design usually focuses upon the optimization of ligand affinity. However, successful drug design also requires the optimization of many other properties. The primary source of structural information for protein-ligand complexes is X-ray crystallography. The uncertainties introduced during the derivation of an atomic model from the experimentally observed electron density data are not always appreciated. Uncertainties in the atomic model can have significant consequences when this model is subsequently used as the basis of manual design, docking, scoring, and virtual screening efforts. Docking and scoring algorithms are currently imperfect. A good correlation between observed and calculated binding affinities is usually only observed only when very large ranges of affinity are considered. Errors in the correlation often exceed the range of affinities commonly encountered during lead optimization. Some structure-based design approaches now involve screening libraries by using technologies based on NMR spectroscopy and X-ray crystallography to discover small polar templates, which are used for further optimization. Such compounds are defined as leadlike and are also sought by more traditional high-throughput screening technologies. Structure-based design and HTS technologies show important complementarity and a degree of convergence.

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“…High log P values correspond to compounds with poor aqueous solubility. Compounds with low log P values have a limited ability to penetrate membrane barriers (56). The relatively lipophilic nature of nifedipine is reflected by a log P value of 2.86 (57) which, coupled with high octanol solubility (approximately 10 mg/mL, Table 1), suggested it as a good model drug because (1) it would partition successfully and (2) the biphasic system would provide sink conditions for dissolution.…”

Section: Results and Discussion Proof Of Conceptmentioning

confidence: 99%

Toward Biorelevant Dissolution: Application of a Biphasic Dissolution Model as a Discriminating Tool for HPMC Matrices Containing a Model BCS Class II Drug

Phillips¹,

Pygall²,

Cooper³

et al. 2012

Dissolution Technol.

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The potential of a biphasic dissolution system to assist with the analysis of controlled-release (CR), Biopharmaceutics Classification System (BCS) Class II pharmaceutical products has been investigated. Use of a biphasic dissolution medium (aqueous/octanol) provided sink conditions and afforded complete dissolution of nifedipine formulated in a CR matrix tablet while maintaining the dosage form in an aqueous environment. This was not possible in a monophasic (aqueousonly) dissolution medium. Consequently, the biphasic model allowed the discrimination of three formulations containing different HPMC loadings while the monophasic medium did not. The performance of the formulations in conventional dissolution media incorporating the inorganic salt dibasic sodium phosphate, the surfactant sodium dodecyl sulfate (SDS), and ethanol as solubility modifiers was assessed. The addition of the salt and surfactant failed to produce complete discrimination in a predictive manner. The use of a hydroalcoholic medium comprising water and ethanol enabled the statistical discrimination of the three formulations but not as effectively as the biphasic medium.

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Design principles for orally bioavailable drugs

Cited by 193 publications

References 48 publications

Synthesis and Evaluation of Bis‐Thiazolium Salts as Potential Antimalarial Drugs

Synthesis and Evaluation of Bis‐Thiazolium Salts as Potential Antimalarial Drugs

Application and Limitations of X‐ray Crystallographic Data in Structure‐Based Ligand and Drug Design

Toward Biorelevant Dissolution: Application of a Biphasic Dissolution Model as a Discriminating Tool for HPMC Matrices Containing a Model BCS Class II Drug

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