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2.
J Med Chem ; 62(16): 7543-7556, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31381331

RESUMO

A quaternary ammonium betaine 7 is described which shows exceptional potency and selectivity (1.4 to >3 logs) for the αvß6 integrin receptor over the other αv integrins as determined in cell adhesion assays. 7 is prepared by remarkably stereoselective methylation, the origins of which are discussed. The chemical, biological, physicochemical, and pharmacokinetic properties of 7 and its docking into αvß6 are described along with related analogues.


Assuntos
Betaína/farmacologia , Integrinas/antagonistas & inibidores , Pirrolidinas/química , Compostos de Amônio Quaternário/farmacologia , Animais , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Betaína/química , Betaína/farmacocinética , Células Cultivadas , Cristalografia por Raios X , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Integrinas/química , Integrinas/metabolismo , Metilação , Modelos Químicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacocinética , Ratos , Estereoisomerismo
3.
Angew Chem Int Ed Engl ; 56(41): 12492-12497, 2017 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-28786545

RESUMO

The uridyl peptide antibiotics (UPAs), of which pacidamycin is a member, have a clinically unexploited mode of action and an unusual assembly. Perhaps the most striking feature of these molecules is the biosynthetically unique 3'-deoxyuridine that they share. This moiety is generated by an unusual, small and monomeric dehydratase, Pac13, which catalyses the dehydration of uridine-5'-aldehyde. Here we report the structural characterisation of Pac13 with a series of ligands, and gain insight into the enzyme's mechanism demonstrating that H42 is critical to the enzyme's activity and that the reaction is likely to proceed via an E1cB mechanism. The resemblance of the 3'-deoxy pacidamycin moiety with the synthetic anti-retrovirals, presents a potential opportunity for the utilisation of Pac13 in the biocatalytic generation of antiviral compounds.

4.
Anal Chem ; 89(3): 1772-1777, 2017 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-28095671

RESUMO

Universal quantitative detection without the need for analyte reference standards would offer substantial benefits in many areas of analytical science. The quantitative capability of high-performance liquid chromatography (HPLC) with charged aerosol detection (CAD) was investigated for 50 compounds with a wide range of physical and chemical properties. It is widely believed that CAD is a mass detector. Quantification of the 50 compounds using a generic calibrant and mass calibration achieved an average error of 11.4% relative to 1H NMR. Correction factors are proposed that estimate the relative surface area of particles in the detector, taking into account the effects of the density and charge of analytes. Performing these corrections and quantifying with surface area calibration, rather than mass, shows considerably improved linearity and uniformity of detection, reducing the average error relative to 1H NMR to 7.1%. The accuracy of CAD quantification was most significantly improved for highly dense compounds, with traditional mass calibration showing an average error of 34.7% and the newly proposed surface area calibration showing an average error of 5.8%.

5.
Org Biomol Chem ; 14(25): 5992-6009, 2016 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-27226381

RESUMO

A diastereoselective synthesis of (S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid (1), a potential therapeutic agent for the treatment of Idiopathic Pulmonary Fibrosis, which is currently undergoing Phase I clinical trials is reported. The key steps in the synthesis involved alkylation of 2-methylnaphthyridine with (R)-N-Boc-3-(iodomethyl)-pyrrolidine, and an asymmetric Rh-catalysed addition of an arylboronic acid to a 4-(N-pyrrolidinyl)crotonate ester. The overall yield of the seven linear step synthesis was 8% and the product was obtained in >99.5% ee proceeding with 80% de. The absolute configuration of 1 was established by an alternative asymmetric synthesis involving alkylation of an arylacetic acid using Evans oxazolidinone chemistry, acylation using the resulting 2-arylsuccinic acid, and reduction. The absolute configuration of the benzylic asymmetric centre was established as (S).


Assuntos
Ácido Butírico/síntese química , Ácido Butírico/farmacologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Integrinas/antagonistas & inibidores , Pirrolidinas/química , Pirrolidinas/farmacologia , Antígenos de Neoplasias , Ácido Butírico/química , Ácido Butírico/uso terapêutico , Técnicas de Química Sintética , Oxirredução , Pirrolidinas/síntese química , Pirrolidinas/uso terapêutico , Estereoisomerismo
6.
Eur J Med Chem ; 115: 14-25, 2016 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-26991939

RESUMO

A number of potent 2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine CCR4 antagonists binding to the extracellular allosteric site were synthesised. (R)-N-(2,4-Dichlorobenzyl)-2-(2-(pyrrolidin-2-ylmethyl)-2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine (R)-(18a) has high affinity in both the [(125)I]-TARC binding assay with a pKi of 8.8, and the [(35)S]-GTPγS functional assay with a pIC50 of 8.1, and high activity in the human whole blood actin polymerisation assay (pA2 = 6.7). The most potent antagonists were also investigated for their ability to induce endocytosis of CCR4 and were found to internalise about 60% of the cell surface receptors, a property which is not commonly shared by small molecule antagonists of chemokine receptors.


Assuntos
Endocitose/efeitos dos fármacos , Pirimidinas/farmacologia , Receptores CCR4/antagonistas & inibidores , Compostos de Espiro/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Receptores CCR4/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade
7.
Bioorg Med Chem ; 20(20): 6097-108, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22985961

RESUMO

5-Aza, 6-aza, 7-aza and 8-aza-phthalazinone, and 5,8-diazaphthalazinone templates were synthesised by stereoselective routes starting from the appropriate pyridine/pyrazine dicarboxylic acids by activation with CDI, reaction with 4-chlorophenyl acetate ester enolate to give a ß-ketoester, which was hydrolysed, and decarboxylated. The resulting ketone was condensed with hydrazine to form the azaphthalazinone core. The azaphthalazinone cores were alkylated with N-Boc-D-prolinol at N-2 by Mitsunobu reaction, de-protected, and then alkylated at the pyrrolidine nitrogen to provide the target H(1) receptor antagonists. All four mono-azaphthalazinone series had higher affinity (pK(i)) for the human H(1) receptor than azelastine, but were not as potent as the parent non-aza phthalazinone. The 5,8-diazaphthalazinone was equipotent with azelastine. The least potent series were the 7-azaphthalazinones, whereas the 5-azaphthalazinones were the most lipophilic. The more hydrophilic series were the 8-aza series. Replacement of the N-methyl substituent on the pyrrolidine with the n-butyl group caused an increase in potency (pA(2)) and a corresponding increase in lipophilicity. Introduction of a ß-ether oxygen in the n-butyl analogues (2-methoxyethyl group) decreased the H(1) pA(2) slightly, and increased the selectivity against hERG. The duration of action in vitro was longer in the 6-azaphthalazinone series. The more potent and selective 6-azaphthalazinone core was used to append an H(3) receptor antagonist fragment, and to convert the series into the long acting single-ligand, dual H(1) H(3) receptor antagonist 44. The pharmacological profile of 44 was very similar to our intranasal clinical candidate 1.


Assuntos
Antagonistas dos Receptores Histamínicos H1/síntese química , Ftalazinas/química , Piridazinas/síntese química , Piridinas/síntese química , Receptores Histamínicos H1/química , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/química , Canais de Potássio Éter-A-Go-Go/metabolismo , Antagonistas dos Receptores Histamínicos H1/química , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Ftalazinas/síntese química , Ftalazinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Pirazinas/química , Piridazinas/química , Piridazinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Receptores Histamínicos H1/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
8.
Magn Reson Chem ; 48(10): 753-62, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20803488

RESUMO

We have developed QUANTAS (QUANTification by Artificial Signal), which is a software-based protocol for concentration measurement by NMR. QUANTAS is an absolute intensity external standard method for quantification by NMR that compensates for various experimental parameters. It is applicable to all nuclei and modern spectrometers. QUANTAS is demonstrated here for (1)H and (19)F NMR, enabling heteronuclear integrals to be compared. It can be applied using fixed probe tuning, matching and pulse length, for samples with the same effective loading on the probe coil as the appropriate reference spectrum. Otherwise, an optimised tuning and matching approach is adopted for every sample together with explicit PULCON (PUlse Length-based CONcentration measurements) absolute intensity corrections.


Assuntos
Espectroscopia de Ressonância Magnética/métodos , Processamento de Sinais Assistido por Computador , Software
9.
J Org Chem ; 67(21): 7319-28, 2002 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-12375961

RESUMO

To prepare in multigram scale new antagonists of the glycine binding site associated to the NMDA receptor, an efficient distereoselective route was set up. The addition of suitable allyltin reagents to chiral N-aryl alpha-imino esters (R-(+)-tert-butyl lactate used as chiral auxiliary), gave the corresponding alpha amino acid-type derivative in high chemical yield and optical purity. This allylation reaction represents a novel example of efficient long-range stereodifferentiation process. In the last part of the synthesis, a regioselective Heck-type cyclization reaction enabled preparation of the target tetrasubstituted exocycle and trisubtituted endocycle double bond derivatives.


Assuntos
Iminas/química , Indóis/síntese química , Pirróis/síntese química , Quinolonas/síntese química , Compostos Alílicos , Catálise , Indicadores e Reagentes , Indóis/química , Metais , Estrutura Molecular , Oxirredução , Pirróis/química , Quinolonas/química , Estereoisomerismo , Relação Estrutura-Atividade
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