Beyond-Rule-of-Five Compounds Are Not Different: In Vitro–In Vivo Extrapolation of Female CD-1 Mouse Clearance Based on Merck Healthcare KGaA Compound Set DOI Creative Commons

Christine K. Maurer,

Zhizhou Fang, Heide Marika Duevel

et al.

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(4), P. 568 - 568

Published: April 14, 2025

Background: Extrapolation of intrinsic clearance from in vitro systems such as liver microsomes or hepatocytes is an established approach to predict preclinical species and humans. A common discussion the literature whether predictive accuracy extrapolations influenced by chemotype these methods are also applicable compounds studied early drug discovery programs. Compounds programs frequently lipophilic show low solubility free fraction plasma, which may pose challenges extrapolation different those final clinical candidates. similar has been raised about residing beyond traditional small-molecule property space, PROTACs© other molecules incompatible with Lipinski’s rule-of-five. Methods: To further enlighten field on matters, we present a study comparing between mouse for set (N = 211) Merck Healthcare pipeline. This was dominated belonging class 2 4 extended classification (ECCS). It contained proportion compliant Lipinski rule-of-five 127) lacking compliance 84). Results: showed no little differences nor bias two groups, average fold error close 1, absolute just over 2, around 50% being within 2-fold >90% 5-fold predicted unbound both systems. Furthermore, significant were observed extremely (down 0.05%) plasma. Conclusions: The vitro–in vivo female CD-1 not affected physicochemical properties.

Language: Английский

Beyond-Rule-of-Five Compounds Are Not Different: In Vitro–In Vivo Extrapolation of Female CD-1 Mouse Clearance Based on Merck Healthcare KGaA Compound Set DOI Creative Commons

Christine K. Maurer,

Zhizhou Fang, Heide Marika Duevel

et al.

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(4), P. 568 - 568

Published: April 14, 2025

Background: Extrapolation of intrinsic clearance from in vitro systems such as liver microsomes or hepatocytes is an established approach to predict preclinical species and humans. A common discussion the literature whether predictive accuracy extrapolations influenced by chemotype these methods are also applicable compounds studied early drug discovery programs. Compounds programs frequently lipophilic show low solubility free fraction plasma, which may pose challenges extrapolation different those final clinical candidates. similar has been raised about residing beyond traditional small-molecule property space, PROTACs© other molecules incompatible with Lipinski’s rule-of-five. Methods: To further enlighten field on matters, we present a study comparing between mouse for set (N = 211) Merck Healthcare pipeline. This was dominated belonging class 2 4 extended classification (ECCS). It contained proportion compliant Lipinski rule-of-five 127) lacking compliance 84). Results: showed no little differences nor bias two groups, average fold error close 1, absolute just over 2, around 50% being within 2-fold >90% 5-fold predicted unbound both systems. Furthermore, significant were observed extremely (down 0.05%) plasma. Conclusions: The vitro–in vivo female CD-1 not affected physicochemical properties.

Language: Английский

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