Benzylamine

Bioorg Med Chem Lett. 2013 Apr 1;23(7):2177-80.

Deconstruction of sulfonamide inhibitors of the urotensin receptor (UT) and design and synthesis of benzylamine and benzylsulfone antagonists.[Pubmed: 23453841]

Potent small molecule antagonists of the urotensin receptor are described.
METHODS AND RESULTS:
These inhibitors were derived via systematically deconstructing a literature inhibitor to understand the basic pharmacophore and key molecular features required to inhibit the protein receptor.
CONCLUSIONS:
The series of Benzylamine and benzylsulfone antagonists herein reported display a combination of nanomolar molecular and cellular potency as well as acceptable in vitro permeability and metabolic stability.

J Physiol Biochem. 2012 Dec;68(4):651-62.

Benzylamine antihyperglycemic effect is abolished by AOC3 gene invalidation in mice but not rescued by semicarbazide-sensitive amine oxidase expression under the control of aP2 promoter.[Pubmed: 22547093]

Semicarbazide-sensitive amine oxidase (SSAO) is a transmembrane enzyme that metabolizes primary amines from endogenous or dietary origin. SSAO is highly expressed in adipose, smooth muscle and endothelial cells. In each of these cell types, SSAO is implicated in different biological functions, such as glucose transport activation, extracellular matrix maturation and leucocyte extravasation, respectively. However, the physiological functions of SSAO and their involvement in pathogenesis remain uncompletely characterized.
METHODS AND RESULTS:
To better understand the role of adipose tissue SSAO, we investigated whether it was necessary and/or sufficient to produce the antihyperglycemic effect of the SSAO-substrate Benzylamine, already reported in mice. Therefore, we crossed SSAO-deficient mice invalidated for AOC3 gene and transgenic mice expected to express human SSAO in an adipocyte-specific manner, under the control of aP2 promoter. The aP2-human AOC3 construct (aP2-hAOC3) was equally expressed in the adipose tissue of mice expressing or not the native murine form and almost absent in other tissues. However, the corresponding SSAO activity found in adipose tissue represented only 20 % that of control mice. As a consequence, the Benzylamine antihyperglycemic effect observed during glucose tolerance test in control was abolished in AOC3-KO mice but not rescued in mice expressing aP2-hAOC3. The capacity of Benzylamine or methylamine to activate glucose uptake in adipocytes exhibited parallel variations in the corresponding genotypes.
CONCLUSIONS:
Although the aP2-hAOC3 construct did not allow a total rescue of SSAO activity in adipose tissue, it could be assessed from our observations that adipocyte SSAO plays a pivotal role in the increased glucose tolerance promoted by pharmacological doses of Benzylamine.

Bioorg Med Chem. 2014 Mar 1;22(5):1558-67.

Synthesis of 2,6-disubstituted benzylamine derivatives as reversible selective inhibitors of copper amine oxidases.[Pubmed: 24529308]

In order to obtain substrate-like inhibitors of copper amine oxidases (CAOs), a class of enzymes involved in important cellular processes as well as in crosslinking of elastin and collagen and removal of biogenic primary amines, we synthesized a set of Benzylamine derivatives properly substituted at positions 2 and 6 and studied their biological activity towards some members of CAOs.
METHODS AND RESULTS:
With Benzylamines 6, 7, 8 containing linear alkoxy groups we obtained reversible inhibitors of Benzylamine oxidase (BAO), very active and selective toward diamine oxidase (DAO), lysyl oxidase (LO) and monoamine oxidase B (MAO B) characterized by a certain toxicity consequent to the crossing of the brain barrier. Poorly toxic, up to very active, reversible inhibitors of BAO, very selective toward DAO, LO and MAO B, were obtained with Benzylamines 10, 11, 12 containing hydrophilic ω-hydroxyalkoxy groups. With Benzylamines 13, 14, 15, containing linear alkyl groups endowed with steric, but not conjugative effects for the absence of properly positioned oxygen atoms, we synthesized moderately active inhibitors of BAO reversible and selective toward DAO, LO and MAO B. The cross examination of the entire biological data brought us to the conclusion that the bioactive synthesized compounds most likely exert their physiological role of reversible inhibitors in consequence of the formation of a plurality of hydrogen bonds or hydrophobic non-covalent interactions with proper sites in the protein.
CONCLUSIONS:
Accordingly, the reported inhibitors may be considered as a set of research tools for general biological studies and the formation of enzyme complexes useful for X-ray structure determinations aimed at the design of more sophisticated inhibitors to always better modulate the protein activity without important side effects.

Spectrochim Acta A Mol Biomol Spectrosc. 2014 May 5;125:297-307.

Spectroscopic, crystallographic and theoretical studies of lasalocid complex with ammonia and benzylamine.[Pubmed: 24562161]

A natural antibiotic--Lasalocid is able to form stable complexes with ammonia and organic amines.
METHODS AND RESULTS:
New complexes of lasalocid with Benzylamine and ammonia were obtained in the crystal forms and studied using X-ray, FT-IR, (1)H NMR, (13)C NMR and DFT methods. These studies have shown that in both complexes the proton is transferred from the carboxylic group to the amine group with the formation of a pseudo-cyclic structure of lasalocid anion complexing the protonated amine or NH4(+) cation.
CONCLUSIONS:
The spectroscopic and DFT studies demonstrated that the structure of the complex formed between Lasalocid and Benzylamine in the solid is also conserved in the solution and gas phase. In contrast, the structure of the complex formed between lasalocid and ammonium cation found in the solid state undergoes dissociation in chloroform solution accompanied with a change in the coordination form of the NH4(+) cation.

J Enzyme Inhib Med Chem. 2014 Apr;29(2):168-74.

Synthesis and carbonic anhydrase isoenzymes I and II inhibitory effects of novel benzylamine derivatives.[Pubmed: 23391138]

Synthesis and carbonic anhydrase inhibitory properties of novel diarylmethylamines 22-25 and sulfonamide derivatives 26-28 were investigated.
METHODS AND RESULTS:
Acylation of methoxy-substituted benzenes with benzene carboxylic acids, reduction of ketones with NaBH4, conversion of alcohols to azides, Pd-C catalyzed hydrogenation of azides afforded title compounds 22-25. Compounds 22, 24 and 25 were converted to sulfonamide derivatives 26-28 with MeSO2Cl. The inhibitory effects of novel Benzylamine derivatives 22-28 were tested on human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes hCA I and II.
CONCLUSIONS:
The results demonstrated that compound 28 was found to be the best inhibitor against both hCA I (Ki: 3.68 µM) and hCA II (Ki: 9.23 µM).