Modulating the strength of hydrogen bond acceptors to achieve low Caco2 efflux for oral bioavailability of PARP inhibitors blocking centrosome clustering.

Autor: Gu C; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States. Electronic address: chungang.gu@astrazeneca.com., Lamb ML; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States. Electronic address: michelle.lamb@astrazeneca.com., Johannes JW; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Sylvester MA; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Eisman MS; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Harrison RA; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Hu H; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Kazmirski S; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Mikule K; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Peng B; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Su N; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Wang W; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Ye Q; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Zheng X; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Lyne PD; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Scott DA; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2016 Oct 01; Vol. 26 (19), pp. 4775-4780. Date of Electronic Publication: 2016 Aug 12.
DOI: 10.1016/j.bmcl.2016.08.030
Abstrakt: During the lead generation and optimization of PARP inhibitors blocking centrosome clustering, it was discovered that increasing hydrogen bond acceptor (HBA) strength improved cellular potency but led to elevated Caco2 and MDR1 efflux and thus poor oral bioavailability. Conversely, compounds with lower efflux had reduced potency. The project team was able to improve the bioavailability by reducing efflux through systematic modifications to the strength of the HBA by changing the electronic properties of neighboring groups, whilst maintaining sufficient acceptor strength for potency. Additionally, it was observed that enantiomers with different potency showed similar efflux, which is consistent with the promiscuity of efflux transporters. Eventually, a balance between potency and low efflux was achieved for a set of lead compounds with good bioavailability which allowed the project to progress towards establishing in vivo pharmacokinetic/pharmacodynamic relationships.
(Copyright © 2016 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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