Detail of "108605-62-5"

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In vitro metabolism studies on the isoxazole ring scission in the anti-inflammatory agent leflunomide to its active a-cyanoenol metabolite A771726: Mechanistic similarities with the cytochrome P450-catalyzed dehydration of aldoximes

In vitro metabolism studies on the isoxazole ring scission in the anti-inflammatory agent leflunomide to its active a-cyanoenol metabolite A771726: Mechanistic similarities with the cytochrome P450-catalyzed dehydration of aldoximes. Kalgutkar, Amit S.; Nguyen, Hang T.; Vaz, Alfin D. N.; Doan, Anke; Dalvie, Deepak K.; Mcleod, Dale G.; Murray, John C. (Departments of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Groton, CT, USA). Drug Metabolism and Disposition, 31(10), 1240-1250 (English) 2003 American Society for Pharmacology and Experimental Therapeutics. CODEN: DMDSAI. ISSN: 0090-9556.In this article, certain chemicals are used. Some of their cas registry numbers are 108605-62-5 and 330597-62-1 DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) The 3-unsubstituted isoxazole ring in the anti-inflammatory drug leflunomide undergoes a unique N-O bond cleavage to the active a-cyanoenol metabolite A771726, which resides in the same oxidn. 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 physiol. conditions, leflunomide was converted to A771726 in rat and human plasma (rat plasma, t1/2 = 36 min; human plasma, t1/2 = 12 min) and whole blood (rat blood, t1/2 = 59 min; human blood, t1/2 = 43 min). Human serum albumin also catalyzed A771726 formation, albeit at a much slower rate (t1/2 = 110 min). Rat and human liver microsomes also demonstrated NADPH-dependent A771726 formation (human liver microsomes, Vmax = 1797 pmol/min/mg and Km = 274 mM). Leflunomide metab. in microsomes was sensitive to furafylline treatment, suggesting P 450 1A2 involvement. 3-Methylleflunomide, which contained a 3-Me 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-Me 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 P 450 1A2 required NADPH, its formation was greatly reduced by oxygen or carbon monoxide, suggesting that the isoxazole ring opening was catalyzed by the P 450-Fe(II) form of the enzyme. A mechanism for the P 450-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 P 450-Fe(II) to the C=N bond or deprotonation of the C3-H, which results in a cleavage of the N-O bond. .

Pulmonary-allergy, dermatological, gastrointestinal & arthritis

Pulmonary-allergy, dermatological, gastrointestinal & arthritis. Leflunomide and malononitriloamides. Silva, Helio Tedesco, Jr.Several substances are used for example 108605-62-5 and 75706-12-6 which are their cas registry numbers.; Morris, Randall Ellis (Nephrology Div., Escola Paulista Medicina, Sao Paulo, Brazil). Expert Opinion on Investigational Drugs, 6(1), 51-64 (English) 1997 Ashley Publications. CODEN: EOIDER. ISSN: 0967-8298. DOCUMENT TYPE: Journal; General Review CA Section: 1 (Pharmacology) A review, with 87 refs. Leflunomide is a new immunomodulatory drug effective in exptl. models of autoimmune diseases and allo- or xenotransplantation. In a Phase II clin. trial leflunomide has shown high tolerability and efficacy in patients with advanced rheumatoid arthritis. The immunomodulatory activity of leflunomide is attributed to its primary metabolite, A77 1726, a malononitriloamide. The in vitro and in vivo mechanisms of action of this class of compds. remain to be completely defined. A77 1726 and several malononitriloamide analogs inhibit T- and B-cell proliferation, suppress Ig prodn., and interfere with cell adhesion. While no one central mol. mechanism of action has been proposed to explain all the effects of the malononitriloamides, inhibition of de novo pyrimidine biosynthesis and inhibition of cytokine- and growth factor-receptor assocd. tyrosine kinase activity are leading hypotheses for the effects of A77 1726 on T- and B-cell proliferation and function. Leflunomide is effective when administered at daily doses of 10 and 25 mg to patients with active rheumatoid arthritis. The improved efficacy at the 25 mg dose is assocd. with a higher incidence of adverse effects (gastrointestinal symptoms, wt. loss, allergic reactions, skin rash, and reversible alopecia). Due to the long plasma half-life of A77 1726 (11-16 days), loading doses are required to achieve steady-state concns. Phase III randomized, placebo- controlled trials using daily doses of 10 or 20 mg are underway in the US and Europe to confirm and extend the results of the Phase II study. Malononitriloamide analogs of A77 1726 are being evaluated for immunosuppressive efficacy in preclin. models of transplantation, because these compds. have a shorter half-life in animals than A77 1726. If these analogs show efficacies similar to leflunomide in these models and have shorter half-lives than A77 1726 in Phase I trials, the preclin. and Phase I data will be used to select the analogs for Phase II trials in organ transplant recipients. .