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1.
Bioorg Chem ; 148: 107489, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38797065

RESUMO

The number of opioid-related overdose deaths and individuals that have suffered from opioid use disorders have significantly increased over the last 30 years. FDA approved maintenance therapies to treat opioid use disorder may successfully curb drug craving and prevent relapse but harbor adverse effects that reduce patient compliance. This has created a need for new chemical entities with improved patient experience. Previously our group reported a novel lead compound, NAT, a mu-opioid receptor antagonist that potently antagonized the antinociception of morphine and showed significant blood-brain barrier permeability. However, NAT belongs to thiophene containing compounds which are known structural alerts for potential oxidative metabolism. To overcome this, 15 NAT derivatives with various substituents at the 5'-position of the thiophene ring were designed and their structure-activity relationships were studied. These derivatives were characterized for their binding affinity, selectivity, and functional activity at the mu opioid receptor and assessed for their ability to antagonize the antinociceptive effects of morphine in vivo. Compound 12 showed retention of the basic pharmacological attributes of NAT while improving the withdrawal effects that were experienced in opioid-dependent mice. Further studies will be conducted to fully characterize compound 12 to examine whether it would serve as a new lead for opioid use disorder treatment and management.


Assuntos
Receptores Opioides mu , Animais , Relação Estrutura-Atividade , Camundongos , Receptores Opioides mu/metabolismo , Receptores Opioides mu/antagonistas & inibidores , Humanos , Estrutura Molecular , Tiofenos/química , Tiofenos/farmacologia , Tiofenos/síntese química , Tiofenos/uso terapêutico , Masculino , Relação Dose-Resposta a Droga , Analgésicos Opioides/farmacologia , Analgésicos Opioides/química , Antagonistas de Entorpecentes/farmacologia , Antagonistas de Entorpecentes/química , Morfina/farmacologia
2.
Acta Pharm Sin B ; 14(5): 1987-2005, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38799621

RESUMO

The N-methyl-d-aspartate (NMDA) receptors, which belong to the ionotropic Glutamate receptors, constitute a family of ligand-gated ion channels. Within the various subtypes of NMDA receptors, the GluN1/2A subtype plays a significant role in central nervous system (CNS) disorders. The present article aims to provide a comprehensive review of ligands targeting GluN2A-containing NMDA receptors, encompassing negative allosteric modulators (NAMs), positive allosteric modulators (PAMs) and competitive antagonists. Moreover, the ligands' structure-activity relationships (SARs) and the binding models of representative ligands are also discussed, providing valuable insights for the clinical rational design of effective drugs targeting CNS diseases.

3.
J Pharmacol Exp Ther ; 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38409113

RESUMO

While agonists of mu (MOR) and kappa (KOR) opioid receptors have analgesic effects, they produce euphoria and dysphoria, respectively. Other side effects include respiratory depression and addiction for MOR agonists and sedation for KOR agonists. We reported that 17-cyclopropylmethyl-3,14ß-dihydroxy-4,5α-epoxy-6ß-{[4'-(2'-cyanopyridyl)]carboxamido}cmorphinan (NCP) displayed potent KOR full agonist and MOR partial agonist activities (58%) with 6.5x KOR-over-MOR selectivity in vitro Herein, we characterized pharmacological effects of NCP in rodents. In mice, NCP exerted analgesic effects against inflammatory pain in both the formalin test and the acetic acid writhing test, with A50 values of 47.6 and 14.4 microg/kg (s.c.), respectively. The analgesic effects in the acetic acid writhing test were mediated by the KOR. NCP at doses much higher than those effective in reducing inflammatory pain did not produce antinociception in the hot plate and tail flick tests, inhibit compound 48/80-induced scratching, cause conditioned place aversion (CPA) or preference, impair rotarod performance, inhibit locomotor activity, cause respiratory depression, or precipitate morphine withdrawal. However, NCP (10~100 microg/kg) inhibited gastrointestinal transit with a maximum of ~40% inhibition. In MOR knockout mice, NCP caused CPA, demonstrating that its lack of CPA is due to combined actions on the MOR and KOR. Following s.c. injection, NCP penetrated into the mouse brain. In rats trained to self-administer heroin, NCP (1~320 microg/kg/infusion) did not function as a reinforcer. Thus, NCP produces potent analgesic effects via KOR without side effects except constipation. Therefore, dual full KOR/partial MOR agonists with moderate KOR-over-MOR selectivity may be promising as non-addictive analgesics for inflammatory pain. Significance Statement Developing non-addictive analgesics is crucial for reducing opioid overdose deaths, minimizing drug misuse, and promoting safer pain management practices. Herein, pharmacology of a potential non-addictive analgesic, NCP, is reported. NCP has full KOR agonist / partial MOR agonist activities with a 6.5 x selectivity for KOR over MOR. Unlike MOR agonists, analgesic doses of NCP do not lead to self-administration or respiratory depression. Furthermore, NCP does not produce aversion, hypolocomotion, or motor incoordination, side effects typically associated with KOR activation.

4.
Pharmaceutics ; 15(11)2023 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-38004527

RESUMO

The synthetic allosteric effector of hemoglobin, TD-7 has been investigated as a potential therapeutic agent for the treatment of sickle cell disease. The pharmacologic activity of TD-7 is due to formation of a Schiff-base interaction between its aldehyde group and the two N-terminal αVal1 amines of hemoglobin, effectively inhibiting sickling of red blood cells. However, TD-7 faces a challenge in terms of poor oral bioavailability due to rapid in-vivo oxidative metabolism of its aldehyde functional group. To address this shortcoming, researches have explored the use of a L-cysteine ethyl ester group to cap the aldehyde group to form a thiazolidine aromatic aldehyde prodrug complex, resulting in the improvement of the metabolic stability of this class of compounds. This report details the synthesis of a thiazolidine prodrug of TD-7, referred to as Pro-7, along with a comprehensive investigation of Pro-7 functional and biological properties. In an in-vitro Hb modification and Hb oxygen affinity studies using normal whole blood, as well as erythrocyte sickling inhibition using sickle whole blood, Pro-7 exhibited a gradual onset but progressive increase in all activities. Additionally, in-vivo pharmacokinetic studies conducted with Sprague Dawley rats demonstrated that Pro-7 can undergo hydrolysis to release TD-7. However, the blood concentration of TD-7 did not reach the desired therapeutic level. These findings suggest that the incorporation of the L-cysteine ethyl ester group to TD-7 represents a promising strategy to enhance the metabolic stability of aromatic aldehydes that could lead to the development of a more effective drug for the treatment of sickle cell disease.

5.
Eur J Med Chem ; 258: 115605, 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37393790

RESUMO

Taking our previously reported HIV-1 NNRTIs BH-11c and XJ-10c as lead compounds, series of novel diarypyrimidine derivatives bearing six-membered non-aromatic heterocycles were designed to improve anti-resistance and drug-like profiles. According to the three rounds of in vitro antiviral activity screening, compound 12g was the most active inhibitor against wild-type and five prevalent NNRTI-resistant HIV-1 strains with EC50 values ranging from 0.024 to 0.0010 µM. This is obviously better than the lead compound BH-11c and the approved drug ETR. Detailed structure-activity relationship was investigated to provide valuable guidance for further optimization. The MD simulation study indicated that 12g could form additional interactions with residues around the binding site in HIV-1 RT, which provided reasonable explanations for its improved anti-resistance profile compared to ETR. Furthermore, 12g showed significant improvement in water solubility and other drug-like properties compared to ETR. The CYP enzymatic inhibitory assay indicated that 12g was unlikely to induce CYP-mediated drug-drug interactions. 12g pharmacokinetics parameters were investigated and it displayed a long half-life of 6.59 h in vivo. The properties of compound 12g make it a promising lead compound for the development of new generation of antiretroviral drugs.


Assuntos
Fármacos Anti-HIV , HIV-1 , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Transcriptase Reversa do HIV , HIV-1/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
6.
Commun Chem ; 6(1): 83, 2023 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-37120482

RESUMO

HIV-1 reverse transcriptase is one of the most attractive targets for the treatment of AIDS. However, the rapid emergence of drug-resistant strains and unsatisfactory drug-like properties seriously limit the clinical application of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Here we show that a series of piperazine sulfonyl-bearing diarylpyrimidine-based NNRTIs were designed to improve the potency against wild-type and NNRTI-resistant strains by enhancing backbone-binding interactions. Among them, compound 18b1 demonstrates single-digit nanomolar potency against the wild-type and five mutant HIV-1 strains, which is significantly better than the approved drug etravirine. The co-crystal structure analysis and molecular dynamics simulation studies were conducted to explain the broad-spectrum inhibitory activity of 18b1 against reverse transcriptase variants. Besides, compound 18b1 demonstrates improved water solubility, cytochrome P450 liability, and other pharmacokinetic properties compared to the currently approved diarylpyrimidine (DAPY) NNRTIs. Therefore, we consider compound 18b1 a potential lead compound worthy of further study.

7.
J Pharm Biomed Anal ; 223: 115152, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36399908

RESUMO

Aromatic aldehydes act as allosteric effectors of hemoglobin (AEH), forming Schiff-base adducts with the protein to increase its oxygen (O2) affinity; a desirable property in sickle cell disease (SCD) treatment, as the high-O2 affinity hemoglobin (Hb) does not polymerize and subsequently prevents erythrocytes sickling. This study reports the development, validation, and application of a weak cation-exchange HPLC assay - quantifying the appearance of Hb-AEH adduct - as a "universal" method, allowing for the prioritization of AEH candidates through an understanding of their Hb binding affinity and kinetics. Concentration- and time-dependent Hb binding profiles of ten AEHs were determined with HPLC, followed by the appropriate non-linear modeling to characterize their steady-state binding affinity (KDss), and binding kinetics second-order association (kon) and first-order dissociation (koff) rate constants. Vanillin-derived AEHs exhibited enhanced binding affinity to Hb, primarily due to their faster kon. Across AEH, kon and koff values are strongly correlated (r = 0.993, n = 7), suggesting that modifications of the AEH scaffold enhanced their interactions with Hb as intended, but inadvertently increased their Hb-AEH adduct dissociation. To our knowledge, the present study is the first to provide valuable insight into Hb binding kinetics of antisickling aromatic aldehydes, and the assay will be a useful platform in screening/prioritizing drug candidates for SCD treatment.


Assuntos
Aldeídos , Hemoglobina A , Cromatografia Líquida de Alta Pressão , Bases de Schiff , Oxigênio
8.
ACS Pharmacol Transl Sci ; 5(11): 1197-1209, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36407950

RESUMO

Mu opioid receptor (MOR) selective antagonists and partial agonists have clinical utility for the treatment of opioid use disorders (OUDs). However, the development of many has suffered due to their poor pharmacokinetic properties and/or rapid metabolism. Our recent efforts to identify MOR modulators have provided 17-cyclopropylmethyl-3,14ß-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3-carboxamido)morphinan (NAQ), a low-efficacy partial agonist, that showed sub-nanomolar binding affinity to the MOR (K i 0.6 nM) with selectivity over the delta opioid receptor (δ/µ 241) and the kappa opioid receptor (κ/µ 48). Its potent inhibition of the analgesic effect of morphine (AD50 0.46 mg/kg) and precipitation of significantly less withdrawal symptoms even at 100-fold greater dose than naloxone represents a promising molecule for further development as a novel OUD therapeutic agent. Therefore, further in vitro and in vivo characterization of its pharmacokinetics and pharmacodynamics properties was conducted to fully understand its pharmaceutical profile. NAQ showed favorable in vitro ADMET properties and no off-target binding to several classes of GPCRs, enzymes, and ion channels. Following intravenous administration, 1 mg/kg dose of NAQ showed a similar in vivo pharmacokinetic profile to naloxone; however, orally administered 10 mg/kg NAQ demonstrated significantly improved oral bioavailability over both naloxone and naltrexone. Abuse liability assessment of NAQ in rats demonstrated that NAQ functioned as a less potent reinforcer than heroin. Chronic 5 day NAQ pretreatment decreased heroin self-administration in a heroin-vs-food choice procedure similar to the clinically used MOR partial agonist buprenorphine. Taken together, these studies provide evidence supporting NAQ as a promising lead to develop novel OUD therapeutics.

9.
Molecules ; 27(20)2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36296435

RESUMO

Sickle cell disease (SCD) is caused by a single-point mutation, and the ensuing deoxygenation-induced polymerization of sickle hemoglobin (HbS), and reduction in bioavailability of vascular nitric oxide (NO), contribute to the pathogenesis of the disease. In a proof-of-concept study, we successfully incorporated nitrate ester groups onto two previously studied potent antisickling aromatic aldehydes, TD7 and VZHE039, to form TD7-NO and VZHE039-NO hybrids, respectively. These compounds are stable in buffer but demonstrated the expected release of NO in whole blood in vitro and in mice. The more promising VZHE039-NO retained the functional and antisickling activities of the parent VZHE039 molecule. Moreover, VZHE039-NO, unlike VZHE039, significantly attenuated RBC adhesion to laminin, suggesting this compound has potential in vivo RBC anti-adhesion properties relevant to vaso-occlusive events. Crystallographic studies show that, as with VZHE039, VZHE039-NO also binds to liganded Hb to make similar protein interactions. The knowledge gained during these investigations provides a unique opportunity to generate a superior candidate drug in SCD with enhanced benefits.


Assuntos
Anemia Falciforme , Hemoglobina Falciforme , Camundongos , Animais , Hemoglobina Falciforme/metabolismo , Antidrepanocíticos/farmacologia , Antidrepanocíticos/uso terapêutico , Óxido Nítrico , Aldeídos/farmacologia , Nitratos , Laminina , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/metabolismo , Ésteres
10.
Biomolecules ; 12(5)2022 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-35625623

RESUMO

5-hydroxyfurfural (5HMF), an allosteric effector of hemoglobin (Hb) with an ability to increase Hb affinity for oxygen has been studied extensively for its antisickling effect in vitro and in vivo, and in humans for the treatment of sickle cell disease (SCD). One of the downstream pathophysiologies of SCD is nitric oxide (NO) deficiency, therefore increasing NO (bio)availability is known to mitigate the severity of SCD symptoms. We report the synthesis of an NO-releasing prodrug of 5HMF (5HMF-NO), which in vivo, is expected to be bio-transformed into 5HMF and NO, with concomitant therapeutic activities. In vitro studies showed that when incubated with whole blood, 5HMF-NO releases NO, as anticipated. When incubated with sickle blood, 5HMF-NO formed Schiff base adduct with Hb, increased Hb affinity for oxygen, and prevented hypoxia-induced erythrocyte sickling, which at 1 mM concentration were 16%, 10% and 27%, respectively, compared to 21%, 18% and 21% for 5HMF. Crystal structures of 5HMF-NO with Hb showed 5HMF-NO bound to unliganded (deoxygenated) Hb, while the hydrolyzed product, 5HMF bound to liganded (carbonmonoxy-ligated) Hb. Our findings from this proof-of-concept study suggest that the incorporation of NO donor group to 5HMF and analogous molecules could be a novel beneficial strategy to treat SCD and warrants further detailed in vivo studies.


Assuntos
Anemia Falciforme , Pró-Fármacos , Hemoglobinas/química , Humanos , Óxido Nítrico , Oxigênio/química , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico
11.
J Med Chem ; 65(6): 4991-5003, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35255683

RESUMO

Opioid-induced constipation (OIC) is a common adverse effect of opioid analgesics. Peripherally acting µ opioid receptor antagonists (PAMORAs) can be applied in the treatment of OIC without compromising the analgesic effects. NAP, a 6ß-N-4-pyridyl-substituted naltrexamine derivative, was previously identified as a potent and selective MOR antagonist mainly acting peripherally but with some CNS effects. Herein, we introduced a highly polar aromatic moiety, for example, a pyrazolyl or imidazolyl ring to decrease CNS MPO scores in order to reduce passive BBB permeability. Four compounds 2, 5, 17, and 19, when administered orally, were able to increase intestinal motility during morphine-induced constipation in the carmine red dye assays. Among them, compound 19 (p.o.) improved GI tract motility by 75% while orally administered NAP and methylnaltrexone showed no significant effects at the same dose. Thus, this compound seemed a promising agent to be further developed as an oral treatment for OIC.


Assuntos
Constipação Induzida por Opioides , Analgésicos Opioides/efeitos adversos , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Humanos , Ligantes , Naltrexona/farmacologia , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/farmacologia , Antagonistas de Entorpecentes/uso terapêutico , Receptores Opioides mu
12.
J Med Chem ; 65(6): 5095-5112, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35255685

RESUMO

The µ opioid receptor (MOR) has been an intrinsic target to develop treatment of opioid use disorders (OUD). Herein, we report our efforts on developing centrally acting MOR antagonists by structural modifications of 17-cyclopropylmethyl-3,14-dihydroxy-4,5α-epoxy-6ß-[(4'-pyridyl) carboxamido] morphinan (NAP), a peripherally acting MOR-selective antagonist. An isosteric replacement concept was applied and incorporated with physiochemical property predictions in the molecular design. Three analogs, namely, 25, 26, and 31, were identified as potent MOR antagonists in vivo with significantly fewer withdrawal symptoms than naloxone observed at similar doses. Furthermore, brain and plasma drug distribution studies supported the outcomes of our design strategy on these compounds. Taken together, our isosteric replacement of pyridine with pyrrole, furan, and thiophene provided insights into the structure-activity relationships of NAP and aided the understanding of physicochemical requirements of potential CNS acting opioids. These efforts resulted in potent, centrally efficacious MOR antagonists that may be pursued as leads to treat OUD.


Assuntos
Morfinanos , Transtornos Relacionados ao Uso de Opioides , Analgésicos Opioides/química , Sistema Nervoso Central , Humanos , Morfinanos/química , Naloxona , Antagonistas de Entorpecentes/farmacologia , Antagonistas de Entorpecentes/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Receptores Opioides mu
13.
Drug Discov Today ; 27(7): 1936-1944, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35182736

RESUMO

Given the substantial cost and low success rate of drug discovery and development, repositioning existing drugs to treat new diseases has gained significant attention in recent years, with potentially lower development costs and shorter time frames. Natural products show great promise in drug repositioning because they have been used for various medical purposes for thousands of years. In this review, we discuss the drug repositioning of six prototypical natural products and their derivatives to reveal new drug-disease associations. We also highlight opportunities and challenges in natural product-based drug repositioning for future reference.


Assuntos
Produtos Biológicos , Reposicionamento de Medicamentos , Descoberta de Drogas
14.
Molecules ; 27(3)2022 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-35164129

RESUMO

Viral infections pose a persistent threat to human health. The relentless epidemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global health problem, with millions of infections and fatalities so far. Traditional approaches such as random screening and optimization of lead compounds by organic synthesis have become extremely resource- and time-consuming. Various modern innovative methods or integrated paradigms are now being applied to drug discovery for significant resistance in order to simplify the drug process. This review provides an overview of newly emerging antiviral strategies, including proteolysis targeting chimera (PROTAC), ribonuclease targeting chimera (RIBOTAC), targeted covalent inhibitors, topology-matching design and antiviral drug delivery system. This article is dedicated to Prof. Dr. Erik De Clercq, an internationally renowned expert in the antiviral drug research field, on the occasion of his 80th anniversary.


Assuntos
Antivirais/farmacologia , Antivirais/uso terapêutico , Descoberta de Drogas/métodos , Desenho de Fármacos/métodos , Desenho de Fármacos/tendências , Descoberta de Drogas/tendências , Reposicionamento de Medicamentos/métodos , Reposicionamento de Medicamentos/tendências , Humanos , Viroses/tratamento farmacológico
15.
J Med Chem ; 64(18): 13604-13621, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34496571

RESUMO

Two series of new pyridyl-bearing fused bicyclic analogues designed to target the dual-tolerant regions of the non-nucleoside reverse transcriptase inhibitor (NNRTI)-binding pocket were synthesized and evaluated for their anti-HIV activities. Several compounds, such as 6, 14, 15, 21, 30, and 33, were found to be potent inhibitors against the wild-type (WT) HIV-1 strain or multiple NNRTI-resistant strains at low nanomolar levels. Detailed structure-activity relationships were obtained by utilizing the variation of moieties within the corresponding pharmacophores. In vitro metabolic stability profiles and some drug-like properties of selected compounds were assessed, furnishing the preliminary structure-metabolic stability relationships. Furthermore, molecular modeling studies elucidated the binding modes of compounds 6, 15, 21, and 30 in the binding pocket of WT, E138K, K103N, or Y181C HIV-1 RTs. These promising compounds can be used as lead compounds and warrant further structural optimization to yield more active HIV-1 inhibitors.


Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 2 Anéis/farmacologia , Piridinas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/metabolismo , Linhagem Celular , Desenho de Fármacos , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Estrutura Molecular , Mutação , Ligação Proteica , Piridinas/síntese química , Piridinas/metabolismo , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade
16.
J Med Chem ; 64(11): 7702-7723, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34027668

RESUMO

Crystal structures of ligand-bound G-protein-coupled receptors provide tangible templates for rationally designing molecular probes. Herein, we report the structure-based design, chemical synthesis, and biological investigations of bivalent ligands targeting putative mu opioid receptor C-C motif chemokine ligand 5 (MOR-CCR5) heterodimers. The bivalent ligand VZMC013 possessed nanomolar level binding affinities for both the MOR and CCR5, inhibited CCL5-stimulated calcium mobilization, and remarkably improved anti-HIV-1BaL activity over previously reported bivalent ligands. VZMC013 inhibited viral infection in TZM-bl cells coexpressing CCR5 and MOR to a greater degree than cells expressing CCR5 alone. Furthermore, VZMC013 blocked human immunodeficiency virus (HIV)-1 entry in peripheral blood mononuclear cells (PBMC) cells in a concentration-dependent manner and inhibited opioid-accelerated HIV-1 entry more effectively in phytohemagglutinin-stimulated PBMC cells than in the absence of opioids. A three-dimensional molecular model of VZMC013 binding to the MOR-CCR5 heterodimer complex is constructed to elucidate its mechanism of action. VZMC013 is a potent chemical probe targeting MOR-CCR5 heterodimers and may serve as a pharmacological agent to inhibit opioid-exacerbated HIV-1 entry.


Assuntos
Desenho de Fármacos , Ligantes , Receptores CCR5/metabolismo , Receptores Opioides mu/metabolismo , Analgésicos Opioides/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Sítios de Ligação , Dimerização , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Maraviroc/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Naltrexona/química , Fito-Hemaglutininas/farmacologia , Ligação Proteica , Receptores CCR5/química , Receptores Opioides mu/química , Internalização do Vírus/efeitos dos fármacos
17.
Bioorg Chem ; 109: 104702, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33631465

RESUMO

In the present study, the role of 3-hydroxy group of a series of epoxymorphinan derivatives in their binding affinity and selectivity profiles toward the opioid receptors (ORs) has been investigated. It was found that the 3-hydroxy group was crucial for the binding affinity of these derivatives for all three ORs due to the fact that all the analogues 1a-e exhibited significantly higher binding affinities compared to their counterpart 3-dehydroxy ones 6a-e. Meanwhile most compounds carrying the 3-hydroxy group possessed similar selectivity profiles for the kappa opioid receptor over the mu opioid receptor as their corresponding 3-dehydroxy derivatives. [35S]-GTPγS functional assay results indicated that the 3-hydroxy group of these epoxymorphinan derivatives was important for maintaining their potency on the ORs with various effects. Further molecular modeling studies helped comprehend the remarkably different binding affinity and functional profiles between compound 1c (NCP) and its 3-dehydroxy analogue 6c.


Assuntos
Morfinanos/química , Morfinanos/farmacologia , Receptores Opioides/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Receptores Opioides/química
18.
Eur J Med Chem ; 213: 113051, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33279288

RESUMO

To yield potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with favorable drug-like properties, a series of novel diarylpyrimidine derivatives targeting the tolerant region I of the NNRTI binding pocket were designed, synthesized and biologically evaluated. The most active inhibitor 10c exhibited outstanding antiviral activity against most of the viral panel, being about 2-fold (wild-type, EC50 = 0.0021 µM), 1.7-fold (K103N, EC50 = 0.0019 µM), and slightly more potent (E138K, EC50 = 0.0075 µM) than the NNRTI drug etravirine (ETR). Additionally, 10c was endowed with relatively low cytotoxicity (CC50 = 18.52 µM). More importantly, 10c possessed improved drug-like properties compared to those of ETR with an increased Fsp3 (Fraction of sp3 carbon atoms) value. Furthermore, the molecular dynamics simulation and molecular docking studies were implemented to reveal the binding mode of 10c in the binding pocket. Taken together, 10c is a promising lead compound that is worth further investigation.


Assuntos
Fármacos Anti-HIV/síntese química , HIV-1/efeitos dos fármacos , Pirimidinas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Fármacos Anti-HIV/farmacologia , Sítios de Ligação , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade
19.
Chem Biol Drug Des ; 97(1): 67-76, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32725669

RESUMO

Taking the previously reported compound BH-7d as the lead, we designed and synthesized a series of piperidinyl-substituted [1,2,4]triazolo[1,5-a]pyrimidines, and their anti-HIV activities as well as cytotoxicities were evaluated. Several compounds exhibited moderate anti-HIV (IIIB) potency, among which 2b was the most active one (EC50  = 4.29 µM). Structure-activity relationships derived from the antiretroviral results were analyzed. Additionally, most compounds demonstrated reduced cytotoxicity (CC50  > 200 µM) compared with those of BH-7d and etravirine. Molecular docking study further revealed the binding conformation of 2b in the binding pocket of HIV-1 reverse transcriptase.


Assuntos
Fármacos Anti-HIV/síntese química , Desenho de Fármacos , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Triazóis/química , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Simulação de Acoplamento Molecular , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Triazóis/metabolismo , Triazóis/farmacologia
20.
Drug Discov Today ; 26(1): 189-199, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33075471

RESUMO

G protein-coupled receptors (GPCRs) have been exploited as primary targets for drug discovery, and GPCR dimerization offers opportunities for drug design and disease treatment. An important strategy for targeting putative GPCR dimers is the use of bivalent ligands, which are single molecules that contain two pharmacophores connected through a spacer. Here, we discuss the selection of pharmacophores, the optimal length and chemical composition of the spacer, and the choice of spacer attachment points to the pharmacophores. Furthermore, we review the most recent advances (from 2018 to the present) in the design, discovery and development of bivalent ligands. We aim to reveal the state-of-the-art design strategy for bivalent ligands and provide insights into future opportunities in this promising field of drug discovery.


Assuntos
Desenho de Fármacos/métodos , Receptores Acoplados a Proteínas G/metabolismo , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Humanos , Ligantes , Multimerização Proteica , Tecnologia Farmacêutica/tendências
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