title: Modulating the strength of hydrogen bond acceptors to achieve low Caco2 efflux for oral bioavailability of PARP inhibitors blocking centrosome clustering.
abstract: 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.
authors: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States. Electronic address: chungang.gu@astrazeneca.com.
authors: Chungang
authors: C
authors: Gu
authors: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States. Electronic address: michelle.lamb@astrazeneca.com.
authors: Michelle L
authors: ML
authors: Lamb
authors: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors: Jeffrey W
authors: JW
authors: Johannes
authors: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors: Mark A
authors: MA
authors: Sylvester
authors: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors: Mark S
authors: MS
authors: Eisman
authors: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors: Rane A
authors: RA
authors: Harrison
authors: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors: Haiqing
authors: H
authors: Hu
authors: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors: Steven
authors: S
authors: Kazmirski
authors: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors: Keith
authors: K
authors: Mikule
authors: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors: Bo
authors: B
authors: Peng
authors: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors: Nancy
authors: N
authors: Su
authors: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors: Wenxian
authors: W
authors: Wang
authors: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors: Qing
authors: Q
authors: Ye
authors: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors: Xiaolan
authors: X
authors: Zheng
authors: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors: Paul D
authors: PD
authors: Lyne
authors: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors: David A
authors: DA
authors: Scott
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D018385:Centrosome / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D006860:Hydrogen Bonding; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors
keywords: Bioavailability; Caco2; Efflux; Hydrogen bond acceptor; P-gp