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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 ; 20(2): 1122-38, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22196514

RESUMO

To identify structurally novel corticotropin-releasing factor 1 (CRF(1)) receptor antagonists, a series of bicyclic core analogs pyrrolo[1,2-b]pyridazines and pyrrolo[2,1-f]triazin-4(3H)-ones, which were designed based on a monocyclic core antagonist, was synthesized and evaluated. Among the compounds tested, 2-difluoromethoxy-4-methylpyridin-5-yl analog 27 was found to show efficacy in a dose-dependent manner in an elevated plus maze test in rats. The discovery process and structure-activity relationship is presented.


Assuntos
Ansiolíticos/química , Ansiolíticos/farmacologia , Piridazinas/química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Triazinas/química , Triazinas/farmacologia , Animais , Ansiolíticos/síntese química , Ansiolíticos/farmacocinética , Masculino , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/farmacocinética
4.
Bioorg Med Chem Lett ; 21(21): 6470-5, 2011 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-21920742

RESUMO

A novel series of pyridyl carboxamide-based CCR5 inhibitors was designed, synthesized, and demonstrated to be highly potent against HIV-1 infection in both HOS and PBL assays. Attempts to evaluate this series of compounds in a rat PK model revealed its instability in rat plasma. A hypothesis for this liability was proposed, and strategies to overcome this issue were pursued, leading to discovery of highly potent 40 and 41, which featured dramatically improved rat PK profiles.


Assuntos
Fármacos Anti-HIV/farmacocinética , Antagonistas dos Receptores CCR5 , Ácidos Carboxílicos/farmacocinética , Amidas/química , Animais , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/química , Ácidos Carboxílicos/sangue , Ácidos Carboxílicos/química , Descoberta de Drogas , Ratos
5.
Bioorg Med Chem ; 19(13): 4028-42, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21658961

RESUMO

Based on the original spirodiketopiperazine design framework, further optimization of an orally available CCR5 antagonist was undertaken. Structural hybridization of the hydroxylated analog 4 derived from one of the oxidative metabolites and the new orally available non-hydroxylated benzoic acid analog 5 resulted in another potent orally available CCR5 antagonist 6a as a clinical candidate. Full details of a structure-activity relationship (SAR) study and ADME properties are presented.


Assuntos
Fármacos Anti-HIV/química , Benzoatos/química , Antagonistas dos Receptores CCR5 , Dicetopiperazinas/química , Administração Oral , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Benzoatos/síntese química , Benzoatos/farmacocinética , Dicetopiperazinas/síntese química , Dicetopiperazinas/farmacocinética , Cães , Avaliação Pré-Clínica de Medicamentos , Cobaias , Haplorrinos , Humanos , Coelhos , Ratos , Receptores CCR5/metabolismo , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 21(4): 1141-5, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21256008

RESUMO

Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency than the corresponding non-hydroxylated compound 2. Structural hybridation of 4 with the orally available analog 5 resulted in another orally-available spirodiketopiperazine CCR5 antagonist 6a that possesses more favorable pharmaceutical profile for use as a drug candidate.


Assuntos
Fármacos Anti-HIV/química , Antagonistas dos Receptores CCR5 , Dicetopiperazinas/química , Compostos de Espiro/química , Administração Oral , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Linhagem Celular Tumoral , Dicetopiperazinas/síntese química , Dicetopiperazinas/farmacocinética , Dicetopiperazinas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Proteína do Núcleo p24 do HIV/metabolismo , HIV-1/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Ratos , Receptores CCR5/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Estereoisomerismo
7.
Bioorg Med Chem ; 18(14): 5208-23, 2010 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-20542438

RESUMO

Using the previously reported novel spirodiketopiperazine scaffold, the design and synthesis of orally available CCR5 antagonists was undertaken. Compounds possessing a carboxylic acid function in the appropriate position showed improved oral exposure (AUC) relative to the initial chemical leads without reduction in the antagonist activity. The optimized compound 40 was found to show potent anti-HIV activity. Full details of structure-activity relationship (SAR) study are presented.


Assuntos
Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/farmacocinética , Antagonistas dos Receptores CCR5 , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Piperazinas/farmacologia , Piperazinas/farmacocinética , Administração Oral , Animais , Fármacos Anti-HIV/química , Disponibilidade Biológica , Células CACO-2 , Humanos , Piperazinas/química , Ratos , Receptores CCR5/metabolismo
9.
J Mol Biol ; 381(4): 956-74, 2008 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-18590744

RESUMO

C-C chemokine receptor 5 (CCR5), a member of G-protein-coupled receptors, serves as a coreceptor for human immunodeficiency virus type 1 (HIV-1). In the present study, we examined the interactions between CCR5 and novel CCR5 inhibitors containing the spirodiketopiperazine scaffolds AK530 and AK317, both of which were lodged in the hydrophobic cavity located between the upper transmembrane domain and the second extracellular loop (ECL2) of CCR5. Although substantial differences existed between the two inhibitors--AK530 had 10-fold-greater CCR5-binding affinity (K(d)=1.4 nM) than AK317 (16.7 nM)-their antiviral potencies were virtually identical (IC(50)=2.1 nM and 1.5 nM, respectively). Molecular dynamics simulations for unbound CCR5 showed hydrogen bond interactions among transmembrane residues Y108, E283, and Y251, which were crucial for HIV-1-gp120/sCD4 complex binding and HIV-1 fusion. Indeed, AK530 and AK317, when bound to CCR5, disrupted these interhelix hydrogen bond interactions, a salient molecular mechanism enabling allosteric inhibition. Mutagenesis and structural analysis showed that ECL2 consists of a part of the hydrophobic cavity for both inhibitors, although AK317 is more tightly engaged with ECL2 than AK530, explaining their similar anti-HIV-1 potencies despite the difference in K(d) values. We also found that amino acid residues in the beta-hairpin structural motif of ECL2 are critical for HIV-1-elicited fusion and binding of the spirodiketopiperazine-based inhibitors to CCR5. The direct ECL2-engaging property of the inhibitors likely produces an ECL2 conformation, which HIV-1 gp120 cannot bind to, but also prohibits HIV-1 from utilizing the "inhibitor-bound" CCR5 for cellular entry--a mechanism of HIV-1's resistance to CCR5 inhibitors. The data should not only help delineate the dynamics of CCR5 following inhibitor binding but also aid in designing CCR5 inhibitors that are more potent against HIV-1 and prevent or delay the emergence of resistant HIV-1 variants.


Assuntos
Antagonistas dos Receptores CCR5 , Membrana Celular/metabolismo , Espaço Extracelular/metabolismo , HIV-1/metabolismo , Receptores CCR5/química , Regulação Alostérica , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Anticorpos Monoclonais , Células CHO , Fusão Celular , Simulação por Computador , Cricetinae , Cricetulus , Proteína gp120 do Envelope de HIV/metabolismo , Humanos , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Proteínas Mutantes/metabolismo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Trítio
10.
Antimicrob Agents Chemother ; 52(6): 2111-9, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18378711

RESUMO

Aplaviroc (AVC), an experimental CCR5 inhibitor, potently blocks in vitro the infection of R5-tropic human immunodeficiency virus type 1 (R5-HIV-1) at subnanomolar 50% inhibitory concentrations. Although maraviroc is presently clinically available, further studies are required to determine the role of CCR5 inhibitors in combinations with other drugs. Here we determined anti-HIV-1 activity using combinations of AVC with various anti-HIV-1 agents, including four U.S. Food and Drug Administration-approved drugs, two CCR5 inhibitors (TAK779 and SCH-C) and two CXCR4 inhibitors (AMD3100 and TE14011). Combination effects were defined as synergistic or antagonistic when the activity of drug A combined with B was statistically greater or less, respectively, than the additive effects of drugs A and A combined and drugs B and B combined by using the Combo method, described in this paper, which provides (i) a flexible choice of interaction models and (ii) the use of nonparametric statistical methods. Synergistic effects against R5-HIV-1(Ba-L) and a 50:50 mixture of R5-HIV-1(Ba-L) and X4-HIV-1(ERS104pre) (HIV-1(Ba-L/104pre)) were seen when AVC was combined with zidovudine, nevirapine, indinavir, or enfuvirtide. Mild synergism and additivity were observed when AVC was combined with TAK779 and SCH-C, respectively. We also observed more potent synergism against HIV-1(Ba-L/104pre) when AVC was combined with AMD3100 or TE14011. The data demonstrate a tendency toward greater synergism with AVC plus either of the two CXCR4 inhibitors compared to the synergism obtained with combinations of AVC and other drugs, suggesting that the development of effective CXCR4 inhibitors may be important for increasing the efficacies of CCR5 inhibitors.


Assuntos
Fármacos Anti-HIV/farmacologia , Benzoatos/farmacologia , Antagonistas dos Receptores CCR5 , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , Piperazinas/farmacologia , Receptores CXCR4/antagonistas & inibidores , Compostos de Espiro/farmacologia , Benzilaminas , Ciclamos , Dicetopiperazinas , Sinergismo Farmacológico , Quimioterapia Combinada , Inibidores da Fusão de HIV/farmacologia , Humanos , Leucócitos Mononucleares/virologia , Replicação Viral/efeitos dos fármacos
12.
J Biol Chem ; 281(18): 12688-98, 2006 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-16476734

RESUMO

We have characterized the structural and molecular interactions of CC-chemokine receptor 5 (CCR5) with three CCR5 inhibitors active against R5 human immunodeficiency virus type 1 (HIV-1) including the potent in vitro and in vivo CCR5 inhibitor aplaviroc (AVC). The data obtained with saturation binding assays and structural analyses delineated the key interactions responsible for the binding of CCR5 inhibitors with CCR5 and illustrated that their binding site is located in a predominantly lipophilic pocket in the interface of extracellular loops and within the upper transmembrane (TM) domain of CCR5. Mutations in the CCR5 binding sites of AVC decreased gp120 binding to CCR5 and the susceptibility to HIV-1 infection, although mutations in TM4 and TM5 that also decreased gp120 binding and HIV-1 infectivity had less effects on the binding of CC-chemokines, suggesting that CCR5 inhibition targeting appropriate regions might render the inhibition highly HIV-1-specific while preserving the CC chemokine-CCR5 interactions. The present data delineating residue by residue interactions of CCR5 with CCR5 inhibitors should not only help design more potent and more HIV-1-specific CCR5 inhibitors, but also give new insights into the dynamics of CC-chemokine-CCR5 interactions and the mechanisms of CCR5 involvement in the process of cellular entry of HIV-1.


Assuntos
Antagonistas dos Receptores CCR5 , Receptores CCR5/metabolismo , Animais , Sítios de Ligação , Células CHO , Cricetinae , Proteína gp120 do Envelope de HIV/química , HIV-1/metabolismo , Humanos , Cinética , Modelos Químicos , Conformação Molecular , Ligação Proteica , Conformação Proteica
13.
J Virol ; 79(4): 2087-96, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15681411

RESUMO

We established human peripheral blood mononuclear cell (PBMC)-transplanted R5 human immunodeficiency virus type 1 isolate JR-FL (HIV-1(JR-FL))-infected, nonobese diabetic-SCID, interleukin 2 receptor gamma-chain-knocked-out (NOG) mice, in which massive and systemic HIV-1 infection occurred. The susceptibility of the implanted PBMC to the infectivity and cytopathic effect of R5 HIV-1 appeared to stem from hyperactivation of the PBMC, which rapidly proliferated and expressed high levels of CCR5. When a novel spirodiketopiperazine-containing CCR5 inhibitor, AK602/ONO4128/GW873140 (molecular weight, 614), was administered to the NOG mice 1 day after R5 HIV-1 inoculation, the replication and cytopathic effects of R5 HIV-1 were significantly suppressed. In saline-treated mice (n = 7), the mean human CD4(+)/CD8(+) cell ratio was 0.1 on day 16 after inoculation, while levels in mice (n = 8) administered AK602 had a mean value of 0.92, comparable to levels in uninfected mice (n = 7). The mean number of HIV-RNA copies in plasma in saline-treated mice were approximately 10(6)/ml on day 16, while levels in AK602-treated mice were 1.27 x 10(3)/ml (P = 0.001). AK602 also significantly suppressed the number of proviral DNA copies and serum p24 levels (P = 0.001). These data suggest that the present NOG mouse system should serve as a small-animal AIDS model and warrant that AK602 be further developed as a potential therapeutic for HIV-1 infection.


Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , HIV-1/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Piperazinas/farmacologia , Compostos de Espiro/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Relação CD4-CD8 , Modelos Animais de Doenças , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/fisiologia , Humanos , Leucócitos Mononucleares/virologia , Camundongos , Camundongos SCID
14.
J Virol ; 78(16): 8654-62, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15280474

RESUMO

We identified a novel spirodiketopiperazine (SDP) derivative, AK602/ONO4128/GW873140, which specifically blocked the binding of macrophage inflammatory protein 1alpha (MIP-1alpha) to CCR5 with a high affinity (K(d) of approximately 3 nM), potently blocked human immunodeficiency virus type 1 (HIV-1) gp120/CCR5 binding and exerted potent activity against a wide spectrum of laboratory and primary R5 HIV-1 isolates, including multidrug-resistant HIV-1 (HIV-1(MDR)) (50% inhibitory concentration values of 0.1 to 0.6 nM) in vitro. AK602 competitively blocked the binding to CCR5 expressed on Chinese hamster ovary cells of two monoclonal antibodies, 45523, directed against multidomain epitopes of CCR5, and 45531, specific against the C-terminal half of the second extracellular loop (ECL2B) of CCR5. AK602, despite its much greater anti-HIV-1 activity than other previously published CCR5 inhibitors, including TAK-779 and SCH-C, preserved RANTES (regulated on activation normal T-cell expressed and secreted) and MIP-1beta binding to CCR5(+) cells and their functions, including CC-chemokine-induced chemotaxis and CCR5 internalization, while TAK-779 and SCH-C fully blocked the CC-chemokine/CCR5 interactions. Pharmacokinetic studies revealed favorable oral bioavailability in rodents. These data warrant further development of AK602 as a potential therapeutic for HIV-1 infection.


Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , HIV-1/efeitos dos fármacos , Piperazinas/química , Piperazinas/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Células CHO , Quimiocina CCL5/metabolismo , Quimiocinas CC/metabolismo , Quimiotaxia de Leucócito , Cricetinae , Farmacorresistência Viral , Proteína gp120 do Envelope de HIV/metabolismo , Infecções por HIV/virologia , HIV-1/metabolismo , Humanos , Leucócitos Mononucleares , Testes de Sensibilidade Microbiana , Piperazinas/síntese química , Piperazinas/metabolismo , Receptores CCR5/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Compostos de Espiro/farmacologia
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