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Identification of New Functional Inhibitors of Acid Sphingomyelinase Using a Structure−Property−Activity Relation Model

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Johannes Kornhuber*^†, Philipp Tripal^†, Martin Reichel^†, Lothar Terfloth^‡, Stefan Bleich^†, Jens Wiltfang^† and Erich Gulbins^£

Department of Psychiatry and Psychotherapy, University of Erlangen, Germany, Molecular Networks, Erlangen, Germany, and Department of Molecular Biology, University of Duisburg

Essen, Germany

J. Med. Chem., 2008, 51 (2), pp 219–237

DOI: 10.1021/jm070524a

Publication Date (Web): November 21, 2007

* To whom correspondence should be addressed. Address: Johannes Kornhuber, M.D., Department of Psychiatry and Psychotherapy, University of Erlangen, Schwabachanlage 6, D-91054 Erlangen, Germany. Tel.: # 49-9131-853-4166 . Fax.: #49-9131-853-4862. E-mail: Johannes.Kornhuber@ uk-erlangen.de., †

Department of Psychiatry and Psychotherapy, University of Erlangen.

, ‡

Molecular Networks, Erlangen.

, £

University of DuisburgEssen.

Section:

Pharmacology

Abstract

Some organic weak bases induce a detachment from inner lysosomal membranes and subsequent inactivation of acid sphingomyelinase (ASM) and thus work as functional ASM inhibitors. The aim of the present investigation was to develop a structure−property−activity relation (SPAR) model in order to specify the structural and physicochemical characteristics of probes capable of functionally inhibiting ASM. High pK_a and high log P values are necessary but not sufficient preconditions for functional inhibition of ASM. The experimental data supported the requirement of an additional factor, which is necessary for functional inhibition of ASM. This factor k is related to the steric hindrance of the most basic nitrogen atom and presumably modulates the free presentation of a protonated nitrogen atom at the inner lysosomal surface. During the course of the study, we characterized 26 new functional ASM inhibitors, including doxepine 63, fluoxetine 104, maprotiline 109, nortriptyline 114, paroxetine 118, sertraline 124, suloctidil 125, and terfenadine 127.

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This article has been cited by 2 ACS Journal articles (2 most recent appear below).

Electronic and Steric Effects: How Do They Work in Ionic Liquids? The Case of Benzoic Acid Dissociation
Francesca D’Anna, Salvatore Marullo, Paola Vitale and Renato Noto
The Journal of Organic Chemistry2010 75 (14), 4828-4834
- Electronic and Steric Effects: How Do They Work in Ionic Liquids? The Case of Benzoic Acid Dissociation
  Francesca D’Anna, Salvatore Marullo, Paola Vitale and Renato Noto
  The Journal of Organic Chemistry2010 75 (14), 4828-4834
  The need to have a measure of the strength of some substituted benzoic acids in ionic liquid solution led us to use the protonation equilibrium of sodium p-nitrophenolate as a probe reaction, which was studied by means of spectrophotometric titration at ...
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Diastereoselective Synthesis of γ-Amino-δ-hydroxy-α,α-difluorophosphonates: A Vehicle for Structure−activity Relationship Studies on SMA-7, a Potent Sphingomyelinase Inhibitor
Takehiro Yamagishi, Shin Muronoi, Sadao Hikishima, Hiroshi Shimeno, Shinji Soeda and Tsutomu Yokomatsu
The Journal of Organic Chemistry2009 74 (16), 6350-6353
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  The Journal of Organic Chemistry2009 74 (16), 6350-6353
  A highly diastereoselective synthesis of 2-amino alcohol derivatives bearing a difluoromethylphosphonothioate group at the 3-position was achieved through LiAlH(O-t-Bu)3-mediated reduction of the corresponding α-amino ketones. The phosphonothioate moiety ...
  Abstract | Full Text HTML | Hi-Res PDF | PDF w/ Links