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Impact of SPR to minimize CNS penetration on peripheral tissue distribution and bioavailability in mice
Author(s) -
Zhou Xin,
Cramer Jeff,
Jones Tim,
Hudson Loyd,
Sawada Geri,
Desai Prashant,
Raub Tom
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb548
Subject(s) - bioavailability , penetration (warfare) , peripheral , chemistry , pharmacology , pharmacokinetics , brain tissue , perfusion , in vivo , biochemistry , biophysics , medicine , biology , engineering , microbiology and biotechnology , operations research
SPR (structure‐property relationship) to reduce CNSpenetration for LY1 was implemented to mitigate the toxicity induced by hittingthe brain target. In a 24‐hr infusion study in mice, increase in hydrogen bondacceptor/donor strength and subsequent Pgp liability (LY2) led to 5‐times lowerKpuu in the brain. Introduction of carboxylic acid (LY3) and increased polarsurface area (PSA) resulted in 25‐times lower Kpuu. Significant increase in PSA for LY4, also a Pgp substrate, did not lead to further reduction in Kpuucompared to LY2 in steady‐state. Peripheral tissue distribution did not differ for LY1 and LY2 in high and low perfusion tissues; whereas the acidic LY3, displayed lower Kpuu in various tissues, including peripheral target tissues. The pharmacokinetics study revealed that the lower permeability of LY3 and LY4 was detrimental to bioavailability after administration of compounds by oralgavage at 10 mg/kg. The results demonstrated that SPR for increased Pg pliability without significant impact on pKa and PSA would minimize brain penetration, and maintain adequate bioavailability and peripheral tissue distribution for efficacy.Compound MW clogP pKa PSA HBD/HBA strength Kpuu, brainLY1 285 1.6 2.2 (most basic) 85 5 0.5 LY2 293 2.0 2.3 (most basic) 85 5.8 0.1 LY3 304 2.2 4.0 (most acidic)2.2 (most basic) 102 8.5 0.02 LY4 339 1.7 10.0 (most acidic)2.3 (most basic) 125 9.3 0.2