A prodrug system for hydroxylamines based on esterase catalysis

Conejo‐García, Ana; Schofield, Christopher J.

doi:10.1016/j.bmcl.2005.06.026

Cited by 13 publications

(6 citation statements)

References 19 publications

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“…Furthermore, M2 was stable to chemical hydrolysis in buffer at acidic and basic pH, ruling out the possibility of an artifact of a chemical hydrolysis in the mobile phase. This was consistent with earlier reports that have demonstrated the hydrolytic cleavage of hydroxamates to the corresponding carboxylic acid (Kobashi et al, 1973;Conejo-Garcia and Schofield, 2005) CP-544439 was also converted to the glucuronide M1 in the rat and dog. It was the primary circulating metabolite in dog plasma (24% of the total radioactivity) and was the only metabolite detected in dog bile.…”

Section: Disposition Of Cp-544439supporting

confidence: 93%

Metabolism Distribution and Excretion of a Matrix Metalloproteinase-13 Inhibitor, 4-[4-(4-Fluorophenoxy)-benzenesulfonylamino]tetrahydropyran-4-carboxylic Acid Hydroxyamide (CP-544439), in Rats and Dogs: Assessment of the Metabolic Profile of CP-544439 in Plasma and Urine of Humans

Dalvie

Cosker²,

Boyden³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The respectively. Metabolic profiling revealed that CP-544439 was primarily metabolized via glucuronidation, reduction, and hydrolysis. Glucuronidation was the primary route of metabolism in dogs, whereas reduction of the hydroxamate moiety was the major pathway in rats. Human plasma and urine obtained from a dose escalation study in healthy human volunteers were also analyzed in this study to assess the metabolism of CP-544439 in humans and ensure that selected animal species were exposed to all major metabolites formed in humans. Analysis suggested that CP-544439 was metabolized via all three pathways in humans consistent with rat and dog; however, the glucuronide conjugate M1 was the major circulating and excretory metabolite in humans. Preliminary in vitro phenotyping studies indicated that glucuronide formation is primarily catalyzed by UGT1A1, 1A3, and 1A9.The matrix metalloproteinases (MMP) are a family of zincdependent enzymes responsible for breaking down extracellular matrix proteins. Overexpression and activation of MMP have been linked to a range of diseases in which the destruction of connective tissue is an important pathological event, such as osteo arthritis (OA) and rheumatoid arthritis, tumor metastasis and angiogenesis, and corneal ulceration (Beckett et al., 1996;Michaelides and Curtin 1999;Rao, 2005). Collagenase 3 (MMP-13) is one type of MMP that is overexpressed in cartilage tissues of OA patients and is very efficient in the degradation of type II collagen. Thus, MMP-13 has been implicated in the pathology of OA. A selective MMP-13 inhibitor should therefore slow down or prevent cartilage breakdown and improve the quality of life of OA patients by retarding loss of function due to joint deterioration.4-[4-(4-Fluorophenoxy)-benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide (CP-544439) (Scheme 1) was designed and synthesized as a selective inhibitor of MMP-13 (IC 50 ϭ 0.8 nM) (Reiter et al., 2004). In vivo studies using a hamster model, in which the cartilage collagen degradation was induced by intra-articular injection of recombinant human MMP-13 (Otterness et al., 2000), demonstrated that oral administration of CP-544439 inhibits degradation of the cartilage collagen with an ED 50 of 14 mg/kg and efficacious plasma concentrations ranging from 0.5 to 1.0 g/ml.Preclinical pharmacokinetic studies of CP-544439 in rats and dogs demonstrated that the clearance of CP-544439 was high in rats (53 ml/min/kg) and moderate in dogs (10 ml/min/kg). The volume of distribution ranged from 1.6 to 2.0 l/kg in the two species, and the terminal elimination half-life was 0.9 and 6.5 h in rats and dogs, Article, publication date, and citation information can be found at

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Section: Disposition Of Cp-544439supporting

confidence: 93%

Metabolism Distribution and Excretion of a Matrix Metalloproteinase-13 Inhibitor, 4-[4-(4-Fluorophenoxy)-benzenesulfonylamino]tetrahydropyran-4-carboxylic Acid Hydroxyamide (CP-544439), in Rats and Dogs: Assessment of the Metabolic Profile of CP-544439 in Plasma and Urine of Humans

Dalvie

Cosker²,

Boyden³

et al. 2008

Drug Metab Dispos

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“…While the latter reaction is known to occur also with less strained lactones under mild conditions, 20 the former reaction is normally performed at high reaction temperatures 20c or with the respective aluminum amides. 21 The facile ring opening with compounds 8a and 8b is the testimony of the higher ring strain of lactones in tricyclic compounds of this type. 22 In summary, a new approach to diastereomerically pure 3-azabicyclo[3.…”

mentioning

confidence: 99%

Conformationally restricted pyrrolidines by intramolecular [2+2] photocycloaddition reactions

et al. 2013

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“…The two lactones were converted to Obenzyl hydroxamates (2a and 2b) via nucleophilic attack by O-benzyl hydroxylamine (Scheme 1). In the previous publications, the general coupling reagent for the coupling of lactones and hydroxylamine was trimethylaluminum (Conejo-Garcia, 2005). However, we found that DMAP-catalyzed ring opening reaction gave a moderate yield (50% and 36%, respectively), and it was enough to get a desired hydroxamate, 2a and 2b.…”

Section: Resultsmentioning

confidence: 71%

Structure-activity relationship studies of novel oxygen-incorporated SAHA analogues

2009

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Novel oxygen-incorporated SAHA (oxa-SAHA) analogues, in which oxygen was inserted in the alkyl linker connecting the hydroxamic acid moiety and amide group, were synthesized and their inhibitory activities on histone deacetylase were evaluated. The most active oxa-SAHA analogue potently inhibited histone deacetylase, almost as potently as SAHA. Various structural modifications in the amide, but not the hydroxamic acid, significantly affected the inhibitory activities of the derivatives. Based on the inhibitory data, the N-phenyl moiety of the amide turned to be a better modification site for enhancing the inhibitory activity.

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A prodrug system for hydroxylamines based on esterase catalysis

Cited by 13 publications

References 19 publications

Metabolism Distribution and Excretion of a Matrix Metalloproteinase-13 Inhibitor, 4-[4-(4-Fluorophenoxy)-benzenesulfonylamino]tetrahydropyran-4-carboxylic Acid Hydroxyamide (CP-544439), in Rats and Dogs: Assessment of the Metabolic Profile of CP-544439 in Plasma and Urine of Humans

Metabolism Distribution and Excretion of a Matrix Metalloproteinase-13 Inhibitor, 4-[4-(4-Fluorophenoxy)-benzenesulfonylamino]tetrahydropyran-4-carboxylic Acid Hydroxyamide (CP-544439), in Rats and Dogs: Assessment of the Metabolic Profile of CP-544439 in Plasma and Urine of Humans

Conformationally restricted pyrrolidines by intramolecular [2+2] photocycloaddition reactions

Structure-activity relationship studies of novel oxygen-incorporated SAHA analogues

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