A New Rational Hypothesis for the Pharmacophore of the Active Metabolite of Leflunomide, a Potent Immunosuppressive Drug

Bertolini, Giorgio; Aquino, Mario; Biffi, Mauro; D'Atri, G; Pierro, Francesco Di; Ferrario, F.; Mascagni, Paolo; Somenzi, F.; Zaliani, Andrea; Leoni, Flavio

doi:10.1021/jm970039n

Cited by 29 publications

(10 citation statements)

References 26 publications

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“…Leflunomide originated as an agricultural fungicide that was later found to be an anti-inflammatory immunomodulator. Upon oral administration, leflunomide is rapidly converted to its active primary metabolite ( 15 ). , Teriflunomide has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH) by binding to a narrow hydrophobic channel of DHODH leading to the active site.…”

Section: Case Studies: Drugs From Biological and Clinical Efforts (Re...mentioning

confidence: 99%

Lead-like Drugs: A Perspective

Raymer

Bhattacharya

2018

J. Med. Chem.

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Lead-like drugs, or drugs below molecular weight 300, are an important and sometimes overlooked component of the current pharmacopeia and contemporary medicinal chemistry practice. To examine the recent state-of-the-art in lead-like drug discovery, we surveyed recent drug approvals from 2011 to 2017 and top 200 prescribed medications, as well as provide case studies on recently approved lead-like drugs. Many of these recent drugs are close analogs of previously known drugs or natural substrates, with a key focus of their medicinal chemistry optimization being the choice of a low molecular weight starting point and maintaining low molecular weight during the optimization. However, the identification of low molecular weight starting points may be limited by the availability of suitable low molecular weight screening sets. To increase the discovery rate of lead-like drugs, we suggest an increased focus on inclusion and prosecution of lead-like starting points in screening libraries.

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Section: Case Studies: Drugs From Biological and Clinical Efforts (Re...mentioning

confidence: 99%

Lead-like Drugs: A Perspective

Raymer

Bhattacharya

2018

J. Med. Chem.

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“…The principal biotransformation pathway of leflunomide in humans involves an N-O bond cleavage on its isoxazole ring, leading to the formation of the 2-cyano-3-oxo-N-[(4-trifluoromethyl)phenyl]butyramide (A771726) metabolite that resides in the same oxidation state as the parent drug ( Fig. 1) (Lucian et al, 1995;Davis et al, 1996;Bertolini et al, 1997;Silva and Morris, 1997;Prakash and Jarvis, 1999;Rozman, 2002). In the case of leflunomide, the isoxazole ring opening to A771726 represents an important biochemical consequence since this metabolite is responsible for the anti-inflammatory and disease-modifying properties of leflunomide (Rozman, 2002).…”

Section: N-[(4-trifluoromethyl)phenyl]-5-methylisoxazole-4-carboxamidmentioning

confidence: 99%

In VITRO METABOLISM STUDIES ON THE ISOXAZOLE RING SCISSION IN THE ANTI-INFLAMMATORY AGENT LEFLUNOMIDE TO ITS ACTIVE Α-Cyanoenol METABOLITE A771726: MECHANISTIC SIMILARITIES WITH THE CYTOCHROME P450-Catalyzed DEHYDRATION OF ALDOXIMES

Kalgutkar

Nguyen²,

Vaz³

et al. 2003

Drug Metab Dispos

108

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:The 3-unsubstituted isoxazole ring in the anti-inflammatory drug leflunomide undergoes a unique N-O bond cleavage to the active ␣-cyanoenol metabolite A771726, which resides in the same oxidation state as the parent. In vitro studies were conducted to characterize drug-metabolizing enzyme(s) responsible for ring opening and to gain insight into the mechanism of ring opening. Under physiological conditions, leflunomide was converted to A771726 in rat and human plasma (rat plasma, t 1/2 ‫؍‬ 36 min; human plasma, t 1/2 ‫؍‬ 12 min) and whole blood (rat blood, t 1/2 ‫؍‬ 59 min; human blood, t 1/2 ‫؍‬ 43 min). Human serum albumin also catalyzed A771726 formation, albeit at a much slower rate (t 1/2 ‫؍‬ 110 min). Rat and human liver microsomes also demonstrated NADPH-dependent A771726 formation (human liver microsomes, V max ‫؍‬ 1,797 pmol/min/mg and K m ‫؍‬ 274 M). Leflunomide metabolism in microsomes was sensitive to furafylline treatment, suggesting P4501A2 involvement. 3-Methylleflunomide, which contained a 3-methyl substituent on the isoxazole ring, was resistant to ring opening in base, plasma, blood, and liver microsomes. In microsomes, two monohydroxylated metabolites were formed, and metabolite identification studies established the 3-and the 5-methyl groups on the isoxazole ring as sites of hydroxylation. These results indicate that the C3-H in leflunomide is essential for ring opening. Although A771726 formation in human liver microsomes or recombinant P4501A2 required NADPH, its formation was greatly reduced by oxygen or carbon monoxide, suggesting that the isoxazole ring opening was catalyzed by the P450Fe(II) form of the enzyme. A mechanism for the P450-mediated ring scission is proposed in which the isoxazole ring nitrogen or oxygen coordinates to the reduced form of the heme followed by charge transfer from P450Fe(II) to the C‫؍‬N bond or deprotonation of the C3-H, which results in a cleavage of the N-O bond.

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“…Leflunomide has very poor affinity for recombinant DHODH. 40,41 Likewise metabolism of ezetimibe results in an active metabolite that is more potent in vivo than the parent molecule. Upon administration ezetimibe is reversibly glucuronidated.…”

Section: ■ Active Metabolitesmentioning

confidence: 99%

“…The drug leflunomide is an immunosuppressive agent that is used to treat rheumatoid arthritis . In vivo, the oxazole ring of leflunomide is opened to a β-keto amide . The β-keto amide, teriflunomide, has micromolar potency against recombinant tyrosine kinases and was also shown to inhibit recombinant dihydroorotate dehydrogenase (DHODH) with nanomolar potency, in line with the cellular and in vivo potency of teriflunomide.…”

Section: Active Metabolitesmentioning

confidence: 99%

Causes and Significance of Increased Compound Potency in Cellular or Physiological Contexts

Schwaid

Cornella-Taracido

2017

J. Med. Chem.

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Compound potency is a key metric that is often used to drive medicinal chemistry programs. Compound potency is also taken into account when identifying the mechanism of action of compounds whose pharmacological target is unknown, particularly when these compounds are identified in phenotypic screens. Often compound potency is determined from assays using recombinantly generated, purified protein. It is well understood in the medicinal chemistry community that potency measured with recombinant enzyme and potency measured in cell may not entirely coincide. Decreases in cellular vs recombinant potency are often anticipated or explainable. What is less often realized is that compound potency can increase in a cellular environment due to several factors including cellular metabolism of compounds, protein-protein interactions, post-translational modifications, and asymmetric intracellular localization of compound. Here we discuss these factors and highlight examples where increases in cellular compound potency were critical to the development of probes or drugs.

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A New Rational Hypothesis for the Pharmacophore of the Active Metabolite of Leflunomide, a Potent Immunosuppressive Drug

Cited by 29 publications

References 26 publications

Lead-like Drugs: A Perspective

Lead-like Drugs: A Perspective

In VITRO METABOLISM STUDIES ON THE ISOXAZOLE RING SCISSION IN THE ANTI-INFLAMMATORY AGENT LEFLUNOMIDE TO ITS ACTIVE Α-Cyanoenol METABOLITE A771726: MECHANISTIC SIMILARITIES WITH THE CYTOCHROME P450-Catalyzed DEHYDRATION OF ALDOXIMES

Causes and Significance of Increased Compound Potency in Cellular or Physiological Contexts

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