Discovery and Optimization of 4-(8-(3-Fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic Acid, an Improved PDE4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease (COPD)

Press, Neil J.; Taylor, Roger; Fullerton, Joseph D.; Tranter, Pamela; McCarthy, Clive; Keller, Thomas H.; Arnold, Nicola; Beer, David; Brown, Lyndon; Cheung, Robert; Christie, Julie; Denholm, Alastair A.; Haberthuer, Sandra; Hatto, Julia; Keenan, Mark; Mercer, Mark; Oakman, Helen; Sahri, Helene; Tuffnell, Andrew R.; Tweed, Morris

doi:10.1021/acs.jmedchem.5b00902

Cited by 14 publications

(11 citation statements)

References 27 publications

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“…The cyclohexane ring offers a topologically conservative substitute that was deployed in the phosphodiesterase-4 (PDE4) inhibitor 47b , which was optimized from the progenitor NVP-ABE171 ( 47a ) (Table ). , The poorly reproducible PK profile of 47a , which was attributed to inherently poor intrinsic aqueous solubility, was of concern in the context of controlling the emetic side effect associated with PDE4 inhibitors in humans. It was recognized that the presence of multiple planar aryl rings was a potential contributing factor to the poor solubility properties since these features would favor close crystal packing and interfere with efficient dissolution.…”

Section: Bioisosteric Replacement Of Para-substituted Phenyl Ringsmentioning

confidence: 99%

“…It was recognized that the presence of multiple planar aryl rings was a potential contributing factor to the poor solubility properties since these features would favor close crystal packing and interfere with efficient dissolution. The strategy adopted to disrupt crystal packing was to truncate the benzo[ c ][1,2,5]oxadiazole ring to a single monosubstituted aromatic ring and to replace the benzoic acid element with a saturated isostere, which ultimately led to the identification of 47b as a clinical candidate. , In this series, only the trans -topography inherent to 47b was described, a function of the facile isomerization of the cis -isomer during saponification of the precursor ethyl ester. , In a phase 1 clinical trial, 47b was well absorbed in both normal healthy volunteers (NHVs) and patients, with both the AUC and C max exhibiting dose-proportionality following single oral doses that ranged from 0.5 to 25 mg in the fed state. The reproducible and predictable PK observed with 47b allowed the design of an escalating dosing regimen while minimizing C max and the associated nausea and vomiting.…”

Section: Bioisosteric Replacement Of Para-substituted Phenyl Ringsmentioning

confidence: 99%

“…109,110 In this series, only the transtopography inherent to 47b was described, a function of the facile isomerization of the cis-isomer during saponification of the precursor ethyl ester. 107,108 In a phase 1 clinical trial, 47b was well absorbed in both normal healthy volunteers (NHVs) and patients, with both the AUC and C max exhibiting doseproportionality following single oral doses that ranged from 0.5 to 25 mg in the fed state. The reproducible and predictable PK observed with 47b allowed the design of an escalating dosing regimen while minimizing C max and the associated nausea and vomiting.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

2021

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The benzene moiety is the most prevalent ring system in marketed drugs, underscoring its historic popularity in drug design either as a pharmacophore or as a scaffold that projects pharmacophoric elements. However, introspective analyses of medicinal chemistry practices at the beginning of the 21st century highlighted the indiscriminate deployment of phenyl rings as an important contributor to the poor physicochemical properties of advanced molecules, which limited their prospects of being developed into effective drugs. This Perspective deliberates on the design and applications of bioisosteric replacements for a phenyl ring that have provided practical solutions to a range of developability problems frequently encountered in lead optimization campaigns. While the effect of phenyl ring replacements on compound properties is contextual in nature, bioisosteric substitution can lead to enhanced potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and the hERG channel.

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Section: Bioisosteric Replacement Of Para-substituted Phenyl Ringsmentioning

confidence: 99%

Section: Bioisosteric Replacement Of Para-substituted Phenyl Ringsmentioning

confidence: 99%

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

2021

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“…Clinical lead 53 was ultimately selected for phase I profiling. 135,136 GlaxoSmithKline reported a furazanyl benzimidazole pharmacophore with broad spectrum kinase inhibition activity 137−139 (Figure 14, compound 61). SAR and in silico modeling identified key H-bonding interactions between the aminofurazan and the highly conserved hinge region of ATPbinding site; 140 the C3-amino group acts as a H-bond donor with the carbonyl of Asp-132 and the furazan N2 acts as an Hbond acceptor with Ile-134.…”

Section: ■ Inflammatory Disordersmentioning

confidence: 99%

Furazans in Medicinal Chemistry

et al. 2021

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Incorporation of heterocycles into drug molecules can enhance physical properties and biological activity. A variety of heterocyclic groups is available to medicinal chemists, many of which have been reviewed in detail elsewhere. Oxadiazoles are a class of heterocycle containing one oxygen and two nitrogen atoms, available in three isomeric forms. While the 1,2,4- and 1,3,4-oxadiazoles have seen widespread application in medicinal chemistry, 1,2,5-oxadiazoles (furazans) are less common. This Review provides a summary of the application of furazan-containing molecules in medicinal chemistry and drug development programs from analysis of both patent and academic literature. Emphasis is placed on programs that reached clinical or preclinical stages of development. The examples provided herein describe the pharmacology and biological activity of furazan derivatives with comparative data provided where possible for other heterocyclic groups and pharmacophores commonly used in medicinal chemistry.

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“…The financial burden due to this disease is around $ 49.8 billion in 2010 in the US [2] . Presently long-acting bronchodilators, long-acting muscarinic antogonists, and NSAIDs are employed to counteract the manifestations of COPD [3][4][5][6] . The phosphodiesterase (PDE) family, represented by four genes, PDE4A, -B, -C, and -D, causes the hydrolysis of phosphodiester bond of cAMP to yield inactive AMP.…”

mentioning

confidence: 99%

kNN-MFA-guided 3D-QSAR on Some PDE4 Inhibitors of Benzylamine derivatives For Chronic Obstructive Pulmonary Disease

Singh¹,

Agrawal²,

Mishra³

et al. 2019

pharmaceutical-sciences

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Singh et al.: kNN-MF Analysis on PDE4 Inhibitors Benzylamine derivatives have recently been demonstrated interesting potential as the treatment for chronic obstructive pulmonary disease via interaction with the PDE4 enzymes. To understand the necessity around the nucleus k-nearest-neighbour molecular field analysis-based 3D-QSAR analysis was performed on a series of 47 compounds. The 3D-QSAR studies were performed using stepwise variable selection k-nearestneighbour molecular field analysis approach; a leave-one-out cross-validated correlation coefficient (q 2) of 0.8805 and a predicted r 2 for the external test (pred_r 2) of 0.6677 were obtained. Points generated in k-nearest-neighbour molecular field analysis 3D-QSAR model were S_1789 (-0.0023,-0.0021), E_14 (0.0271, 0.03699). Results showed positive range indicating that positive electrostatic potential is favourable for increase in the activity and hence a less electronegative substituent group is preferred in lattice point 14 (around R 1). Negative range indicates that negative steric potential is favourable for increase in the activity and hence less bulky substituent group is preferred at lattice point. The information rendered by 3D-QSAR models lead to a better understanding of structural requirements for PDE4 inhibitors and help in the design of novel potent molecules.

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Discovery and Optimization of 4-(8-(3-Fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic Acid, an Improved PDE4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease (COPD)

Cited by 14 publications

References 27 publications

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

Furazans in Medicinal Chemistry

kNN-MFA-guided 3D-QSAR on Some PDE4 Inhibitors of Benzylamine derivatives For Chronic Obstructive Pulmonary Disease

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