Source Name: 2011_White

Literature Information

Literature Title On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds
Doi 10.1038/nchembio.664
Research Group
  1. Department of Chemistry and Biochemistry, University of California Santa Cruz
  2. Beth Israel Deaconess Medical Center
  3. Department of Pharmaceutical Chemistry, University of California San Francisco
  4. Pharmacokinetics and Drug Metabolism, Groton Laboratories, Pfizer Inc.
  5. Worldwide Medicinal Chemistry, Groton Laboratories, Pfizer Inc.
  6. -
  7. -
  8. -
  9. -
Data Number 10
Minimum Molecular Weight 712.9
Maximum Molecular Weight 1202.6


Assay Information 1

Assay Type RRCK
Permeability Type logPapp
Membrane Measurement Direction (Exclude PAMPA) Apical to Basolateral (AB)
Assay Detail Cell permeability was determined using RRCK cells (Pfizer, Inc. Groton, CT). RRCK cells were generated in house as a subclone of Madin-Darby Canine Kidney wild-type (MDCK-WT) cells that displayed low expression of endogenous p-glycoprotein (approximately 1-2% of MDCK-WT cells, based on mRNA level). Cells were cultured in minimal essential medium α with supplements and passaged when 70-80% confluent. Cell monolayer flux studies were conducted five days after seeding in 24-well transwell inserts (RRCK in 1.0 µm pore size (Becton Dickinson, Cowley, UK)) at 4.2 x 10^4 cells/cm^2. Donor and acceptor solutions were prepared from HBSS containing HEPES at 20 mM, pH 7.4.
Stock solutions of test compounds were prepared at 10 mM in DMSO and used to prepare donor solutions of 2 µM compound in 0.05% (v/v) DMSO. Apparent permeability (Papp) was determined in apical to basolateral (AB) direction in triplicate by incubating with compound for 2 h at 37˚C. Samples of the medium were analyzed by liquid-chromatography tandem mass spectrometry (LCMS/MS). Papp values were calculated according to the equation Papp = (Q/t) x 1/C_0 x 1/A, where Q is the sampled concentration in the acceptor compartment, t is the incubation time, C_0 is the initial concentration in the donor compartment, and A is the area of the filter of the transwell plate.


Assay Information 2

Assay Type -
Permeability Type -
Membrane Measurement Direction (Exclude PAMPA) -
Assay Detail -