The Role of Intramolecular Reactions and Chemical Degradation in the Apparent Biotransformation Pathways of a Series of SYK Inhibitors.

التفاصيل البيبلوغرافية
العنوان:	The Role of Intramolecular Reactions and Chemical Degradation in the Apparent Biotransformation Pathways of a Series of SYK Inhibitors.
المؤلفون:	Calle B; DMPK (B.C., S.M., S.W., A.P.) and Medicinal Chemistry (B.B., C.D., E.L.), Oncology R&D, AstraZeneca, Cambridge, United Kingdom and DMPK, Oncology R&D, AstraZeneca, Boston, Massachusetts (U.S.)., Barlaam B; DMPK (B.C., S.M., S.W., A.P.) and Medicinal Chemistry (B.B., C.D., E.L.), Oncology R&D, AstraZeneca, Cambridge, United Kingdom and DMPK, Oncology R&D, AstraZeneca, Boston, Massachusetts (U.S.)., Diène C; DMPK (B.C., S.M., S.W., A.P.) and Medicinal Chemistry (B.B., C.D., E.L.), Oncology R&D, AstraZeneca, Cambridge, United Kingdom and DMPK, Oncology R&D, AstraZeneca, Boston, Massachusetts (U.S.)., Lenz E; DMPK (B.C., S.M., S.W., A.P.) and Medicinal Chemistry (B.B., C.D., E.L.), Oncology R&D, AstraZeneca, Cambridge, United Kingdom and DMPK, Oncology R&D, AstraZeneca, Boston, Massachusetts (U.S.)., Martin S; DMPK (B.C., S.M., S.W., A.P.) and Medicinal Chemistry (B.B., C.D., E.L.), Oncology R&D, AstraZeneca, Cambridge, United Kingdom and DMPK, Oncology R&D, AstraZeneca, Boston, Massachusetts (U.S.)., Sarkar U; DMPK (B.C., S.M., S.W., A.P.) and Medicinal Chemistry (B.B., C.D., E.L.), Oncology R&D, AstraZeneca, Cambridge, United Kingdom and DMPK, Oncology R&D, AstraZeneca, Boston, Massachusetts (U.S.)., Wilkinson S; DMPK (B.C., S.M., S.W., A.P.) and Medicinal Chemistry (B.B., C.D., E.L.), Oncology R&D, AstraZeneca, Cambridge, United Kingdom and DMPK, Oncology R&D, AstraZeneca, Boston, Massachusetts (U.S.)., Pike A; DMPK (B.C., S.M., S.W., A.P.) and Medicinal Chemistry (B.B., C.D., E.L.), Oncology R&D, AstraZeneca, Cambridge, United Kingdom and DMPK, Oncology R&D, AstraZeneca, Boston, Massachusetts (U.S.) andrew.pike@astrazeneca.com.
المصدر:	Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2024 Jun 17; Vol. 52 (7), pp. 626-633. Date of Electronic Publication: 2024 Jun 17.
نوع المنشور:	Journal Article
اللغة:	English
بيانات الدورية:	Publisher: American Society for Pharmacology and Experimental Therapeutics, etc.] Country of Publication: United States NLM ID: 9421550 Publication Model: Electronic Cited Medium: Internet ISSN: 1521-009X (Electronic) Linking ISSN: 00909556 NLM ISO Abbreviation: Drug Metab Dispos Subsets: MEDLINE
أسماء مطبوعة:	Original Publication: [Bethesda, Md., etc., American Society for Pharmacology and Experimental Therapeutics, etc.]
مواضيع طبية MeSH:	Syk Kinase/metabolism , Syk Kinase/antagonists & inhibitors , Biotransformation* , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism, Humans ; Protein Kinase Inhibitors/metabolism ; Microsomes, Liver/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors ; Pyrazoles/metabolism
مستخلص:	In vitro metabolism studies of the spleen tyrosine kinase inhibitors AZ-A and AZ-B identified four unusual metabolites. M1 (mass-to-charge ratio 411) was formed by both molecules and was common to several analogs (AZ-C to AZ-H) sharing the same core structure, appearing to derive from the complete loss of a pendent 3,4-diaminotetrahydropyran ring and pyrazole ring cleavage resulting in a nonobvious metabolite. M2-M4 were formed by AZ-A and a subset of the other compounds only and apparently resulted from a sequential loss of H 2 from parent. Initial attempts to isolate M3 for identification were unsuccessful due to sample degradation, and it was subsequently found that M2 and M3 underwent sequential chemical degradation steps to M4. M4 was successfully isolated and shown by mass spectrometry and NMR spectroscopy to be a tricyclic species incorporating the pyrazole and the 3,4-diaminotetrahydropyran groups. We propose that this arises from an intramolecular reaction between the primary amine on the tetrahydropyran and a putative epoxide intermediate on the adjacent pyrazole ring, evidence for which was generated in a β -mercaptoethanol-trapping experiment. The loss of the tetrahydropyran moiety observed in M1 was found to be enhanced in an analog that was unable to undergo the intramolecular reaction step, leading us to propose two possible reaction pathways originating from the reactive intermediate. Ultimately, we conclude that the apparently complex and unusual metabolism of this series of compounds likely resulted from a single metabolic activation step forming an epoxide intermediate, which subsequently underwent intramolecular rearrangement and/or chemical degradation to form the final observed products. SIGNIFICANCE STATEMENT: The current work provides an unusual biotransformation example showing the potential for intramolecular reactions and chemical degradation to give the appearance of complex metabolism arising from a single primary route of metabolism. (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)
المشرفين على المادة:	EC 2.7.10.2 (Syk Kinase) EC 2.7.10.1 (Protein-Tyrosine Kinases) EC 2.7.10.2 (SYK protein, human) 0 (Protein Kinase Inhibitors) 0 (Intracellular Signaling Peptides and Proteins) 0 (Pyrazoles)
تواريخ الأحداث:	Date Created: 20240429 Date Completed: 20240617 Latest Revision: 20240702
رمز التحديث:	20240702
DOI:	10.1124/dmd.124.001659
PMID:	38684371
قاعدة البيانات:	MEDLINE

الوصف
تدمد:	1521-009X
DOI:	10.1124/dmd.124.001659