Using the Golden Triangle to optimize clearance and oral absorption

Johnson, Ted W.; Dress, Klaus R.; Edwards, Martin P.

doi:10.1016/j.bmcl.2009.08.045

Cited by 256 publications

(190 citation statements)

References 23 publications

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“…1,2 In studies of extensive datasets of small molecules, the fundamental properties of molecular size, lipophilicity, shape and polarity have been correlated, to varying degrees, with solubility 3 , membrane permeability 4 , metabolic stability, 5,6 receptor promiscuity, 7 in vivo toxicity, 8,9 and attrition 10,11 in drug development pipelines.…”

Section: Introductionmentioning

confidence: 99%

The role of ligand efficiency metrics in drug discovery

Hopkins

Keserü

Leeson

et al. 2014

Nat Rev Drug Discov

907

932

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Summary Ligand efficiency measures quantify the molecular properties, particularly size and lipophilicity, of small molecules that are required to gain binding affinity to a drug target. For example, ligand efficiency, is the binding free energy per heavy atom count (LE = G/HA) and lipophilic ligand efficiency (LLE = pIC 50 or KicLogP/D). There are additional efficiency measures for groups in a molecule, and for combinations of size and lipophilicity. The application of ligand efficiency metrics has been widely reported in the selection and optimisation of fragments, hits, and leads. In particular, optimisation of lipophilic ligand efficiency shows that it is possible to increase affinity and reduce lipophilicity at the same time, even with challenging 'lipophile-preferring' targets. Mean ligand efficiency measures of molecules acting at a specific target, when combined with their drug-like physical properties, is a practical means of estimating target 'druggability.' This is exemplified with 480 targetassay pairs from the primary literature. Across these targets correlations between biological activity in vitro and physical properties are generally weak, showing that increasing activity by increasing physical properties is not always necessary. Charles H. ReynoldsCharles Reynolds is currently President of Gfree Bio, a modeling and structure-based design company in AbstractThe judicious application of ligand or binding efficiencies, which quantify the molecular properties required to gain binding affinity for a drug target, is gaining traction in the selection and optimisation of fragments, hits, and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimised ligand efficiency values for their target. Optimising ligand efficiencies based on both molecular size and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the molecular inflation that pervades current practice in medicinal chemistry, and to increase the developability of drug candidates.

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Section: Introductionmentioning

confidence: 99%

The role of ligand efficiency metrics in drug discovery

Hopkins

Keserü

Leeson

et al. 2014

Nat Rev Drug Discov

907

932

View full text Add to dashboard Cite

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“…Passive membrane diffusion is considered to be the major contributing process [25]. Recent analyses continue to demonstrate the significance of the non-specific permeation mechanisms governed by molecular properties (namely molecular size and polarity) [16].…”

Section: Lipophilicity and Oral Absorptionmentioning

confidence: 99%

“…Log clearance (log Cl) was largest for a cLogP > 5, less pronounced for cLogP 3-5, and most favorable for a cLogP < 3. Johnson et al [16] analyzed permeability and clearance data for 47,018 Pfizer compounds and observed broad trends for favorable clearance and permeability compared to MW and log D. Using lipophilicity determination, they identified a "golden triangle" of MW and log D values for optimal permeability and metabolic stability. Figure 4 shows permeable and stable compounds in blue and compounds failing permeability or metabolic stability in grey against MW and log D. Compounds with favorable clearance and permeability properties are clustered within this "golden triangle" of MW and log D. …”

Section: Lipophilicity and Clearancementioning

confidence: 99%

Leveraging chromatography based physicochemical properties for efficient drug design

Goetz

Shalaeva²

2018

ADMET DMPK

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<p class="ADMETabstracttext">Applications of chromatography derived lipophilicity, polarity, and 3D concepts such as conformational states, exposed polarity and intramolecular hydrogen bonds (IMHB), are discussed along with recently developed methods for incorporating these concepts into drug design strategies. In addition, the drug design process is described with examples and practices used at Pfizer, as well as experimental and computed parameters used for parallel optimization of properties leading to drug candidate nominations.</p>

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“…Physicochemical properties of orally bioavailable drugs Over the last decade, the number of drugs reaching the market has continued to decrease with the rate of attrition rising to as much as 98% [14][15][16][17][18][19][20]. One noticeable trend during this timeframe is that the molecular weight and lipophilicity of molecules entering clinical studies has continued to increase [15].…”

Section: Introductionmentioning

confidence: 99%

“…Since then, a number of investigators have generated more quantitatively correlated subsets of molecular physicochemical properties related to the absorption, solubility, permeability, oral bioavailability, target specificity, and toxicity of drugs and Additional information on the properties of drug-like molecules can be found in [74][75][76] clinically evaluated molecules [15][16][17][18][19][20][21][22][23]. These parameters have been used to assess the relative probability of success of clinical lead optimization research for specific drug-like compounds that have demonstrated proof of concept in subsequent clinical testing [15][16][17][18][19][20][21][22][23]. Recently, Wager et al [24] analyzed currently marketed drugs for a variety of central nervous system (CNS) disorders and developed a multi-parameter optimization (MPO) score, which is calculated from six in silico physicochemical properties (ClogP, ClogD, TPSA, MW, HBD, and pK a ).…”

Section: Introductionmentioning

confidence: 99%

P2X receptor antagonists for pain management: examination of binding and physicochemical properties

Gum

Wakefield

Jarvis

2011

Purinergic Signalling

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Enhanced sensitivity to noxious stimuli and the perception of non-noxious stimuli as painful are hallmark sensory perturbations associated with chronic pain. It is now appreciated that ATP, through its actions as an excitatory neurotransmitter, plays a prominent role in the initiation and maintenance of chronic pain states. Mechanistically, the ability of ATP to drive nociceptive sensitivity is mediated through direct interactions at neuronal P2X3 and P2X2/3 receptors. Extracellular ATP also activates P2X4, P2X7, and several P2Y receptors on glial cells within the spinal cord, which leads to a heightened state of neural-glial cell interaction in ongoing pain states. Following the molecular identification of the P2 receptor superfamilies, selective small molecule antagonists for several P2 receptor subtypes were identified, which have been useful for investigating the role of specific P2X receptors in preclinical chronic pain models. More recently, several P2X receptor antagonists have advanced into clinical trials for inflammation and pain. The development of orally bioavailable blockers for ion channels, including the P2X receptors, has been traditionally difficult due to the necessity of combining requirements for target potency and selectivity with suitable absorption distribution, metabolism, and elimination properties. Recent studies on the physicochemical properties of marketed orally bioavailable drugs, have identified several parameters that appear critical for increasing the probability of achieving suitable bioavailability, central nervous system exposure, and acceptable safety necessary for clinical efficacy. This review provides an overview of the antinociceptive pharmacology of P2X receptor antagonists and the chemical diversity and drug-like properties for emerging antagonists of P2X3, P2X2/3, P2X4, and P2X7 receptors. Keywords

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Using the Golden Triangle to optimize clearance and oral absorption

Cited by 256 publications

References 23 publications

The role of ligand efficiency metrics in drug discovery

The role of ligand efficiency metrics in drug discovery

Leveraging chromatography based physicochemical properties for efficient drug design

P2X receptor antagonists for pain management: examination of binding and physicochemical properties

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