Second basic pKa: An overlooked parameter in predicting phospholipidosis-inducing potential of diamines

Hiroki Sakai; Hidekazu Inoue; Kenji Murata; Tetsuya Toba; Naohiro Takemoto; Takahiro Matsumoto; Takeo Kawabata

doi:10.1016/j.bmcl.2019.126933

Second basic pKa: An overlooked parameter in predicting phospholipidosis-inducing potential of diamines

Bioorg Med Chem Lett. 2020 May 1;30(9):126933. doi: 10.1016/j.bmcl.2019.126933. Epub 2020 Jan 2.

Authors

Hiroki Sakai¹, Hidekazu Inoue², Kenji Murata², Tetsuya Toba², Naohiro Takemoto², Takahiro Matsumoto², Takeo Kawabata³

Affiliations

¹ Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. Electronic address: sakai.hiroki.xu@daiichisankyo.co.jp.
² Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
³ Institute for Chemical Research, Kyoto University Uji, Kyoto 611-0011, Japan.

PMID: 32044185
DOI: 10.1016/j.bmcl.2019.126933

Abstract

In this paper, we present the phospholipidosis-inducing potential (PLIP) of forty fragment-sized diamines derived from N-benzyl-4-(methylamino)piperidine and discuss the relationship between their PLIP and the physicochemical properties. Our results demonstrate that the previously reported methods are not suitable for predicting the PLIP of fragment-sized diamines; the second basic pKa can distinguish PLIP-positive diamines from PLIP-negative diamines more accurately than ClogP or most basic pKa. To the best of our knowledge, this is the first report describing the relationship between PLIP and second basic pKa.

Keywords: Diamine; Phospholipidosis; Second basic pKa.

MeSH terms

Diamines / adverse effects
Diamines / chemistry
Diamines / pharmacology*
Hydrogen-Ion Concentration
Lipidoses / chemically induced*
Molecular Structure
Structure-Activity Relationship

Substances

Diamines