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1.
ACS Med Chem Lett ; 8(12): 1281-1286, 2017 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-29259748

RESUMO

Scaffold hopping from the amide group of lead compound ONO-7300243 (1) to a secondary alcohol successfully gave a novel chemotype lysophosphatidic acid receptor 1 (LPA1) antagonist 4. Wash-out experiments using rat isolated urethra showed that compound 4 possesses a tight binding feature to the LPA1 receptor. Further modification of two phenyl groups of 1 to pyrrole and an indane moiety afforded an optimized compound ONO-0300302 (19). Despite its high i.v. clearance, 19 inhibited significantly an LPA-induced increase of intraurethral pressure (IUP) in rat (3 mg/kg, p.o.) and dog (1 mg/kg, p.o.) over 12 h. Binding experiments with [3H]-ONO-0300302 suggest that the observed long duration action is because of the slow tight binding character of 19.

2.
ACS Med Chem Lett ; 7(10): 913-918, 2016 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-27774128

RESUMO

Lysophosphatidic acid (LPA) evokes various physiological responses through a series of G protein-coupled receptors known as LPA1-6. A high throughput screen against LPA1 gave compound 7a as a hit. The subsequent optimization of 7a led to ONO-7300243 (17a) as a novel, potent LPA1 antagonist, which showed good efficacy in vivo. The oral dosing of 17a at 30 mg/kg led to reduced intraurethral pressure in rats. Notably, this compound was equal in potency to the α1 adrenoceptor antagonist tamsulosin, which is used in clinical practice to treat dysuria with benign prostatic hyperplasia (BPH). In contrast to tamsulosin, compound 17a had no impact on the mean blood pressure at this dose. These results suggest that LPA1 antagonists could be used to treat BPH without affecting the blood pressure. Herein, we report the hit-to-lead optimization of a unique series of LPA1 antagonists and their in vivo efficacy.

3.
Bioorg Med Chem ; 11(8): 1901-13, 2003 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-12659776

RESUMO

Synthesis and structure-activity relationship (SAR) study of L-amino acid-based N-type calcium channel blockers are described. The compounds synthesized were evaluated for inhibitory activity against both N-type and L-type calcium channels focusing on selectivity to reduce cardiovascular side effects due to blocking of L-type calcium channels. In the course of screening of our compound library, N-(t-butoxycarbonyl)-L-aspartic acid derivative 1a was identified as an initial lead compound for a new series of N-type calcium channel blockers, which inhibited calcium influx into IMR-32 human neuroblastoma cells with an IC(50) of 3.4 microM. Compound 1a also exhibited blockade of N-type calcium channel current in electrophysiological experiment using IMR-32 cells (34% inhibition at 10 microM, n=3). As a consequence of conversion of amino acid residue of 1a, compound 12a, that include N-(t-butoxycarbonyl)-L-cysteine, was found to be a potent N-type calcium channel blocker with an IC(50) of 0.61 microM. Thus, L-cysteine was selected as a potential structural motif for further modification. Optimization of C- and N-terminals of L-cysteine using S-cyclohexylmethyl-L-cysteine as a central scaffold led to potent and selective N-type calcium channel blocker 21f, which showed improved inhibitory potency (IC(50) 0.12 microM) and 12-fold selectivity for N-type calcium channels over L-type channels.


Assuntos
Aminoácidos/química , Aminoácidos/farmacologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/metabolismo , Animais , Cálcio/química , Cálcio/metabolismo , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Tipo N/química , Canais de Cálcio Tipo N/efeitos dos fármacos , Cisteína/química , Cisteína/farmacologia , Eletrofisiologia/métodos , Humanos , Concentração Inibidora 50 , Camundongos , Neuroblastoma/metabolismo , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologia , Células Tumorais Cultivadas
4.
Bioorg Med Chem Lett ; 12(17): 2267-9, 2002 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-12161113

RESUMO

This study was performed to determine the structure-activity relationships (SAR) of L-cysteine based N-type calcium channel blockers. Basic nitrogen was introduced into the C-terminal lipophilic moiety of L-cysteine with a view toward improvement of its physicochemical properties. L-Cysteine derivative 9 was found to be a potent and selective N-type calcium channel blocker with IC(50) of 0.33 microM in calcium influx assay using IMR-32 cells and was 15-fold selective for N-type calcium channels over L-type channels. Compound 9 showed improved oral analgesic efficacy in the rat formalin induced pain model and the rat chronic constriction injury (CCI) model, which is one of the most reliable models of chronic neuropathic pain, without any significant effect on blood pressure or neurological behavior.


Assuntos
Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio Tipo N/efeitos dos fármacos , Cisteína/análogos & derivados , Dor/tratamento farmacológico , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/química , Analgésicos/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/farmacologia , Constrição Patológica , Avaliação Pré-Clínica de Medicamentos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Dor/induzido quimicamente , Ratos , Relação Estrutura-Atividade , Equivalência Terapêutica
5.
Bioorg Med Chem Lett ; 12(6): 915-8, 2002 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-11958993

RESUMO

Synthesis and structure-activity relationship (SAR) studies of L-cysteine-based N-type calcium channel blockers are described. In the course of exploring SAR of the N- and C-terminal substituents, the L-cysteine derivative was found to be a potent N-type calcium channel blocker with an IC(50) value of 0.14 microM on IMR-32 assay. Compound showed 12-fold selectivity for N-type over L-type calcium channels on AtT-20 assay.


Assuntos
Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio Tipo N/efeitos dos fármacos , Cisteína/química , Bloqueadores dos Canais de Cálcio/farmacologia , Cisteína/farmacologia , Humanos , Concentração Inibidora 50 , Relação Estrutura-Atividade , Células Tumorais Cultivadas , ômega-Conotoxinas/química , ômega-Conotoxinas/farmacologia
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