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. 2024 Jan 23;16(2):158. doi: 10.3390/pharmaceutics16020158

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© 2024 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

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Use of the selective CDK7 inhibitor LDC4297 as the source for generation of novel covalently binding CDK7-directed warheads. (A) Chemical linkage of an acceptor for the Michael 1,4 addition reaction was performed to generate QRS compounds 6, 7, and 9. Through the covalent binding of host target CDK7, a block of virus-supportive functions was achieved, and further details on this antiviral strategy were described elsewhere (a,b [43]; c,d, this study, and Yu et al., in preparation; d–f [43,67]; f–h [46,66]). (B) Determination of in vitro eADME parameters (early adsorption-distribution-metabilism-excretion) and pharmacokinetics (PK) parameters, including mean plasma concentrations in vivo (male CD-1^® mice). For intraperitoneal (i.p.) in vivo applications, the vehicles 30% HP-β-cyclodextrin or 5% Transcutol [52] proved to be most suitable.

Use of the selective CDK7 inhibitor LDC4297 as the source for generation of novel covalently binding CDK7-directed warheads. (A) Chemical linkage of an acceptor for the Michael 1,4 addition reaction was performed to generate QRS compounds 6, 7, and 9. Through the covalent binding of host target CDK7, a block of virus-supportive functions was achieved, and further details on this antiviral strategy were described elsewhere (a,b [43]; c,d, this study, and Yu et al., in preparation; d–f [43,67]; f–h [46,66]). (B) Determination of in vitro eADME parameters (early adsorption-distribution-metabilism-excretion) and pharmacokinetics (PK) parameters, including mean plasma concentrations in vivo (male CD-1^® mice). For intraperitoneal (i.p.) in vivo applications, the vehicles 30% HP-β-cyclodextrin or 5% Transcutol [52] proved to be most suitable.