Modulation of Pharmacologically Relevant Properties of Piperidine Derivatives by Functional Groups in an Equatorial or Axial β‐Position to the Amino Group

Abstract

Thirteen epimeric pairs of 5‐substituted N‐piperonyl‐3‐phenylpiperidine derivatives were synthesized in order to explore the stereospecific modulation of basicity, lipophilicity, aqueous solubility, and membrane permeation by functional groups in equatorial or axial positions beta to the amine unit. While this comprehensive data set provides enhanced insight into multiple factors that affect basicity and lipophilicity, it fills an important knowledge gap, providing a frame of reference for the property‐based design of bioactive compounds. Impacts on amine basicity are very pronounced for the β‐equatorial functional groups and parallel basicity‐lowering effects known for acyclic amine derivatives. For β‐axial functional groups, the basicity‐lowering effects are generally decreased, with the nitrile group as the only exception. Basicity and lipophilicity modulations observed for β‐axial functional groups are quite diverse and rationalized in terms of intramolecular hydrogen bonding, dipolar interactions, and special solvation effects. Aqueous solubility and (artificial) membrane permeability are discussed with reference to lipophilicity.

Discovery of Balovaptan, a Vasopressin 1a Receptor Antagonist for the Treatment of Autism Spectrum Disorder

“…After learning that even subtly increasing the polarity of the substituent R in the 4-position of the cyclohexane ring could confer P-gp mediated efflux, we chose to use the compound with the lowest efflux ratio, the phenyl cyclohexyl ether 37, a highly potent V1a antagonist with good selectivity against hV2 and hOT receptors, as a template to explore the scope of the N-substituent. As summarized in Table 3 potency at the human V1a receptor was retained with a number of replacements of the N-methyl group, with the exception of hydrogen (42) and BOC (48). Beyond this the secondary amine 42 turned out to be a substrate of P-gp with an efflux ratio of 4.3.…”

“…41 log D. Water/octanol distribution coefficients or effective lipophilicities (log D) were determined as previously described. 42 phMRI. Animals and Animal Preparation.…”

Determination of pKa Values for Some Benzimidazole and Imidazole Group Drugs Using the Reversed-Phase Liquid Chromatography Method

“…N -Alkyl substitution of piperidine produces a tertiary amine with the basicity characteristically decreased from that of the parent secondary amine (p K a ≅ 11.1). Further substitution at the piperidine ring or in the N -alkyl group decreased the amine basicity of the piperidine ring . Moreover, there is a great substituent effect of fluorophenyl on the p K a value of the benzimidazole ring …”

“…Further substitution at the piperidine ring or in the N-alkyl group decreased the amine basicity of the piperidine ring. 32 Moreover, there is a great substituent effect of fluorophenyl on the pK a value of the benzimidazole ring. 33 The benzimidazole compound thiabendazole (4-(1Hbenzimidazole-2-yl)-1,3-thiazole) has extended conjugation through the ethylene bridge (CH 2 CH 2 ).…”

Quinoline, with the active site of 8‐hydroxyl, efficiently inhibits Micropterus salmoides rhabdovirus (MSRV) infection in vitro and in vivo

“…Although some lead compounds have undefined mechanisms, most compounds exhibit excellent bioactivity. Significantly, the bioactivity depends not only on the molecular integrity, but also on interconnected functional groups (Han et al., 2020; Huang et al., 2020; Mao et al., 2016; Martino et al., 2017; Schnider et al., 2020). Thus, the modifiability and findability of the active site should be the standard development of lead compounds.…”