A Highly Potent, Orally Active Imidazo[4,5-b]pyridine Biphenyl Acylsulfonamide (MK-996; L-159,282): A New AT1-Selective Angiotensin II Receptor Antagonist

Chakravarty, Prasun K.; Naylor, Elizabeth M.; Chen, Anna; Chang, Raymond S.L.; Chen, Tsing-Bau; Faust, Kristy A.; Lotti, Victor J.; Kivlighn, Salah D.; Gable, Robert A.

doi:10.1021/jm00050a002

Cited by 51 publications

(23 citation statements)

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“…Mizuhara et al [74] proposed an innovative method to fabricate these NPs using a zwitterionic alkoxyphenyl acylsulfonamide coating (Figure 11(A)). The acylsulfonamide plays a role similar to that of carboxylic acid groups in response to changes in pH value [75]. The pH responsivity of acylsulfonamide group is controlled by the functional group attached to the sulfonyl group.…”

Section: Corona-free Interfaces For High-yield Targeting and Deliverymentioning

confidence: 99%

Emerging understanding of the protein corona at the nano-bio interfaces

2016

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Upon entering the physiological environment, nanoparticles (NPs) are immediately surrounded by a complex and tightly bound layer of biomolecules, or '(hard) protein corona'. The corona controls NP fate in vivo and becomes the interface with cells. One of nanomedicine's central goals is to make NPs capable of active targeting in both imaging and therapy. If the NP is not designed correctly, the resulting corona can cause mistargeting and aberrant biodistribution, unanticipated toxicity, and low therapeutic efficacy. Here we present groundbreaking concepts about nanobio interactions and discuss approaches to bypass protein corona issues and thus enhance the efficacy of NPs.

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Section: Corona-free Interfaces For High-yield Targeting and Deliverymentioning

confidence: 99%

Emerging understanding of the protein corona at the nano-bio interfaces

2016

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“…At least in principle, a severe bioactivation liability associated with acyl glucuronidation might be circumvented during drug development by bioisosteric substitution of the carboxyl group with a tetrazole or hydroxamic function 74. No substitution is likely to be without its own pharmacological and metabolic limitations but potentially excessive drug clearance via N ‐glucuronidation of a tetrazole moiety can be avoided by using the alternative, glucuronidation‐resistant, acyl sulphonamide group 75. The marked susceptibility of the hydroxamic acid group to being metabolised to a carboxyl function can be avoided by preparing instead metabolically stable reversed hydroxamates, such as those of indomethacin 76, an NSAID that forms a reactive acyl glucuronide 28.…”

Section: The Carboxylic Acid Group As a Pharmacophore And Bioisosterementioning

confidence: 99%

Acyl glucuronides: the good, the bad and the ugly

Regan

Maggs

Hammond

et al. 2010

Biopharm & Drug Disp

166

145

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Acyl glucuronidation is the major metabolic conjugation reaction of most carboxylic acid drugs in mammals. The physiological consequences of this biotransformation have been investigated incompletely but include effects on drug metabolism, protein binding, distribution and clearance that impact upon pharmacological and toxicological outcomes. In marked contrast, the exceptional but widely disparate chemical reactivity of acyl glucuronides has attracted far greater attention. Specifically, the complex transacylation and glycation reactions with proteins have provoked much inconclusive debate over the safety of drugs metabolised to acyl glucuronides. It has been hypothesised that these covalent modifications could initiate idiosyncratic adverse drug reactions. However, despite a large body of in vitro data on the reactions of acyl glucuronides with protein, evidence for adduct formation from acyl glucuronides in vivo is limited and potentially ambiguous. The causal connection of protein adduction to adverse drug reactions remains uncertain. This review has assessed the intrinsic reactivity, metabolic stability and pharmacokinetic properties of acyl glucuronides in the context of physiological, pharmacological and toxicological perspectives. Although numerous experiments have characterised the reactions of acyl glucuronides with proteins, these might be attenuated substantially in vivo by rapid clearance of the conjugates. Consequently, to delineate a relationship between acyl glucuronide formation and toxicological phenomena, detailed pharmacokinetic analysis of systemic exposure to the acyl glucuronide should be undertaken adjacent to determining protein adduct concentrations in vivo. Further investigation is required to ascertain whether acyl glucuronide clearance is sufficient to prevent covalent modification of endogenous proteins and consequentially a potential immunological response.

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“…15 We chose this group as the negatively charged part of the zwitterionic ligand, with pH-responsiveness controlled by the functional group attached to the sulfonyl group. AuNP 1 features an aryl acylsulfonamide while AuNP 2 provides an alkyl analog (Figure 1).…”

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confidence: 99%