Buffa, Vanessa ; Meyners, Christian ; Sugiarto, Wisely Oki ; Bauder, Michael ; Gaali, Steffen ; Hausch, Felix (2024)
1,4‐Pyrazolyl‐Containing SAFit‐Analogues are Selective FKBP51 Inhibitors With Improved Ligand Efficiency and Drug‐Like Profile.
In: ChemMedChem, 2024, 19 (17)
doi: 10.26083/tuprints-00028297
Artikel, Zweitveröffentlichung, Verlagsversion

Kurzbeschreibung (Abstract)

The FK506 binding protein 51 (FKBP51) is an appealing drug target due to its role in several diseases such as depression, anxiety, chronic pain and obesity. Towards this, selectivity versus the close homolog FKBP52 is essential. However, currently available FKBP51‐selective ligands such as SAFit2 are too large and lack drug‐like properties. Here, we present a structure activity relationship (SAR) analysis of the pipecolic ester moiety of SAFit1 and SAFit2, which culminated in the discovery of the 1,4‐pyrazolyl derivative 23 d, displaying a binding affinity of 0.077 μM for FKBP51, reduced molecular weight (541.7 g/mol), lower hydrophobicity (cLogP=3.72) and higher ligand efficiency (LE=0.25). Cocrystal structures revealed the importance of the 1,4‐ and 1,3,4‐ substitution patterns of the pyrazole ring versus the 1,4,5 arrangement.

Typ des Eintrags:	Artikel
Erschienen:	2024
Autor(en):	Buffa, Vanessa ; Meyners, Christian ; Sugiarto, Wisely Oki ; Bauder, Michael ; Gaali, Steffen ; Hausch, Felix
Art des Eintrags:	Zweitveröffentlichung
Titel:	1,4‐Pyrazolyl‐Containing SAFit‐Analogues are Selective FKBP51 Inhibitors With Improved Ligand Efficiency and Drug‐Like Profile
Sprache:	Englisch
Publikationsjahr:	12 November 2024
Ort:	Darmstadt
Publikationsdatum der Erstveröffentlichung:	2 September 2024
Ort der Erstveröffentlichung:	Weinheim
Verlag:	Wiley-VCH
Titel der Zeitschrift, Zeitung oder Schriftenreihe:	ChemMedChem
Jahrgang/Volume einer Zeitschrift:	19
(Heft-)Nummer:	17
Kollation:	23 Seiten
DOI:	10.26083/tuprints-00028297
URL / URN:	https://tuprints.ulb.tu-darmstadt.de/28297
Zugehörige Links:	Supplements Verlags-DOI
Herkunft:	Zweitveröffentlichung DeepGreen
Kurzbeschreibung (Abstract):	The FK506 binding protein 51 (FKBP51) is an appealing drug target due to its role in several diseases such as depression, anxiety, chronic pain and obesity. Towards this, selectivity versus the close homolog FKBP52 is essential. However, currently available FKBP51‐selective ligands such as SAFit2 are too large and lack drug‐like properties. Here, we present a structure activity relationship (SAR) analysis of the pipecolic ester moiety of SAFit1 and SAFit2, which culminated in the discovery of the 1,4‐pyrazolyl derivative 23 d, displaying a binding affinity of 0.077 μM for FKBP51, reduced molecular weight (541.7 g/mol), lower hydrophobicity (cLogP=3.72) and higher ligand efficiency (LE=0.25). Cocrystal structures revealed the importance of the 1,4‐ and 1,3,4‐ substitution patterns of the pyrazole ring versus the 1,4,5 arrangement.
Alternatives oder übersetztes Abstract:	Alternatives Abstract Sprache SAFit2 is the current gold standard for the selective inhibition of the FK506-binding protein 51 (FKBP51). While being a useful tool compound, its poor physicochemical profile and large size prevent SAFit2 from being pursued as a drug candidate. In the present structure-activity relationship (SAR) study, the newly discovered 1,4-pyrazolyl analogue 23 d retains selective binding to FKBP51 and shows an improved drug-like profile with lower lipophilicity (cLogP), reduced molecular weight (MW) and increased ligand efficiency compared to SAFit2. Englisch
Freie Schlagworte:	FKBP, FKBP51, SAFit, selective FKBP51 antagonists, pyrazole
ID-Nummer:	Artikel-ID: e202400264
Status:	Verlagsversion
URN:	urn:nbn:de:tuda-tuprints-282976
Sachgruppe der Dewey Dezimalklassifikatin (DDC):	500 Naturwissenschaften und Mathematik > 540 Chemie 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin, Gesundheit
Fachbereich(e)/-gebiet(e):	07 Fachbereich Chemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie > Strukturbasierte Wirkstoffforschung 07 Fachbereich Chemie > Clemens-Schöpf-Institut
Hinterlegungsdatum:	12 Nov 2024 13:21
Letzte Änderung:	13 Nov 2024 06:48
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• 1,4‐Pyrazolyl‐Containing SAFit‐Analogues are Selective FKBP51 Inhibitors With Improved Ligand Efficiency and Drug‐Like Profile. (deposited 12 Nov 2024 13:21) [Gegenwärtig angezeigt]
  • 1,4‐pyrazolyl‐containing SAFit‐analogues are selective FKBP51 inhibitors with improved ligand efficiency and drug‐like profile. (deposited 13 Nov 2024 06:49)

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