RESUMO
The widespread emergence of antibiotic resistance, including multidrug resistance in Gram-negative (G-) bacterial pathogens, poses a critical challenge to the current antimicrobial armamentarium. Antibody-drug conjugates (ADCs), primarily used in anticancer therapy, offer a promising treatment alternative due to their ability to deliver a therapeutic molecule while simultaneously activating the host immune response. The Cloudbreak platform is being used to develop ADCs to treat infectious diseases, composed of a therapeutic targeting moiety (TM) attached via a noncleavable linker to an effector moiety (EM) to treat infectious diseases. In this proof-of-concept study, 21 novel dimeric peptidic molecules (TMs) were evaluated for activity against a screening panel of G- pathogens. The activities of the TMs were not impacted by existing drug resistance. Potent TMs were conjugated to the Fc fragment of human IgG1 (EM), resulting in 4 novel ADCs. These ADCs were evaluated for immunoprophylactic efficacy in a neutropenic mouse model of deep thigh infection. In colistin-sensitive infections, 3 of the 4 ADCs offered protection similar to that of therapeutically dosed colistin, while CTC-171 offered enhanced protection. The efficacy of these ADCs was unchanged in colistin-resistant infections. Together, these results indicate that the ADCs used here are capable of potent binding to G- pathogens regardless of lipopolysaccharide (LPS) modifications that otherwise lead to antibiotic resistance and support further exploration of ADCs in the treatment of infections caused by drug-resistant G- bacteria.
Assuntos
Colistina , Infecções por Bactérias Gram-Negativas , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Modelos Animais de Doenças , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Lipopolissacarídeos , CamundongosRESUMO
Piperazinebenzylamine derivatives from trans-4-(4-chlorophenyl)tetrahydrothiophene-3-carboxylic acid 6 and its S-oxide 7 and sulfone 8, and the tetrahydrofuran 9 and its two regioisomers 11 and 13 were synthesized and studied for their binding affinities at the human melanocortin-4 receptor. These five-membered ring constrained compounds possessed similar or lower potency compared to the acyclic analogs.
Assuntos
Furanos/síntese química , Furanos/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Receptor Tipo 4 de Melanocortina/efeitos dos fármacos , Tiofenos/síntese química , Tiofenos/farmacologia , Técnicas de Química Combinatória , Furanos/química , Humanos , Ligantes , Estrutura Molecular , Piperazinas/química , Tiofenos/químicaRESUMO
Based on 3-phenylpropionamides, a series of 3-arylpyrrolidine-2-carboxamide derivatives was designed and synthesized to study the effect of cyclizations as melanocortin-4 receptor ligands. It was found that the 2R,3R-pyrrolidine isomer possessed the most potent affinity among the four stereoisomers.
Assuntos
Desenho de Fármacos , Pirrolidinas/síntese química , Receptor Tipo 4 de Melanocortina/agonistas , Administração Oral , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Ciclização , Estrutura Molecular , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Ratos , Receptor Tipo 4 de Melanocortina/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 13b displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-pyrrolidine 13b-1 possessed a Ki of 1.0 nM and an EC50 of 3.8 nM, while its 3R,4S-isomer 13b-2 exhibited a Ki of 4.7 and an IC50 of 64 nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 13b-1 also demonstrated efficacy in a diet-induced obesity model in rats.
Assuntos
Pirrolidinas/química , Pirrolidinas/farmacologia , Receptor Tipo 4 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Animais , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Cinética , Masculino , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of potent zwitterionic uracil GnRH antagonists were discovered that showed reduced liability for CYP3A4 enzyme inhibition.
Assuntos
Química Farmacêutica/métodos , Citocromo P-450 CYP3A/química , Íons , Receptores LHRH/antagonistas & inibidores , Uracila/análogos & derivados , Desenho de Fármacos , Hormônio Liberador de Gonadotropina/química , Humanos , Cinética , Modelos Químicos , Estrutura Molecular , Peptídeos/química , Estereoisomerismo , Relação Estrutura-Atividade , Uracila/químicaRESUMO
A series of 2-piperazine-alpha-isopropylbenzylamine derivatives were synthesized and characterized as melanocortin-4 receptor (MC4R) antagonists. Attaching an amino acid to benzylamines 7 significantly increased their binding affinity, and the resulting compounds 8-12 bound selectively to MC4R over other melanocortin receptor subtypes and behaved as functional antagonists. These compounds were also studied for their permeability using Caco-2 cell monolayers and metabolic stability in human liver microsomes. Most compounds exhibited low permeability and high efflux ratio possibly due to their high molecular weights. They also showed moderate metabolic stability which might be associated with their moderate to high lipophilicity. Pharmacokinetic properties of these MC4R antagonists, including brain penetration, were studied in mice after oral and intravenous administrations. Two compounds identified to possess high binding affinity and selectivity, 10d and 11d, were studied in a murine cachexia model. After intraperitoneal (ip) administration of 1mg/kg dose, mice treated with 10d had significantly more food intake and weight gain than the control animals, demonstrating efficacy by blocking the MC4 receptor. Similar in vivo effects were also observed when 11d was dosed orally at 20mg/kg. These results provide further evidence that a potent and selective MC4R antagonist has potential in the treatment of cancer cachexia.
Assuntos
Benzilaminas/farmacologia , Caquexia/tratamento farmacológico , Piperazinas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Animais , Benzilaminas/síntese química , Benzilaminas/química , Células CACO-2 , Carcinoma Pulmonar de Lewis , Cristalografia por Raios X , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Haplorrinos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Conformação Molecular , Piperazinas/síntese química , Piperazinas/química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de Tempo , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Benzylamine and pyridinemethylamine derivatives were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor (MC4R). These compounds were also profiled in rodents for their pharmacokinetic properties. Two compounds with diversified profiles in chemical structure, pharmacological activities, and pharmacokinetics, 10 and 12b, showed efficacy in an established murine cachexia model. For example, 12b had a K(i) value of 3.4 nM at MC4R, was more than 200-fold selective over MC3R, and had a good pharmacokinetic profile in mice, including high brain penetration. Moreover, 12b was able to stimulate food intake in the tumor-bearing mice and reverse their lean body mass loss. Our results provided further evidence that a potent and selective MC4R antagonist with appropriate pharmacokinetic properties might potentially be useful for the treatment of cancer cachexia.
Assuntos
Amidas/síntese química , Benzilaminas/síntese química , Piperazinas/síntese química , Piridinas/síntese química , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Amidas/farmacocinética , Amidas/farmacologia , Animais , Benzilaminas/farmacocinética , Benzilaminas/farmacologia , Caquexia/tratamento farmacológico , Caquexia/etiologia , Carcinoma Pulmonar de Lewis/complicações , Linhagem Celular , Cristalografia por Raios X , AMP Cíclico/metabolismo , Desenho de Fármacos , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Transplante de Neoplasias , Piperazinas/farmacocinética , Piperazinas/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A potent and selective antagonist of the melanocortin-4 receptor, 1-[2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-6-methylphenyl]-4-[(2R)-methyl-3-(4-chlorophenyl)propionyl]piperazine (10d), was identified from a series piperazinebenzylamine attached with a N,N-dimethyl-beta-alanine side chain. This compound possessed high water solubility and exhibited good metabolic profiles. In animals, 10d showed moderate to good oral bioavailability and promoted food intake in tumor-bearing mice after oral administration.
Assuntos
Caquexia/tratamento farmacológico , Piperazinas/síntese química , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , beta-Alanina/análogos & derivados , Administração Oral , Animais , Disponibilidade Biológica , Caquexia/etiologia , AMP Cíclico/metabolismo , Cães , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Transplante de Neoplasias , Neoplasias Experimentais/complicações , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , beta-Alanina/síntese química , beta-Alanina/farmacocinética , beta-Alanina/farmacologiaRESUMO
A series of trans-N-alkyl-4-(4-chlorophenyl)pyrrolidine-3-carboxamides of piperazinecyclohexanemethylamines was synthesized and characterized for binding and function at the melanocortin-4 receptor (MC4R), and several potent benzylamine derivatives were identified. Compound 18 v was found to bind MC4R with potent affinity (K(i)=0.5 nM) and high selectivity over the other melanocortin subtypes and behaved as a functional antagonist (IC(50)=48 nM).
Assuntos
Amidas/química , Ácidos Carboxílicos/química , Compostos Clorados/síntese química , Cicloexanos/química , Piperazinas/química , Pirrolidinas/química , Receptor Tipo 4 de Melanocortina/metabolismo , Compostos Clorados/química , Cicloexanos/farmacologia , Ligantes , Estrutura Molecular , Piperazina , Receptor Tipo 4 de Melanocortina/agonistas , Relação Estrutura-AtividadeRESUMO
A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 20f-1 and 20f-2 displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-compound 20f-1 possessed a K(i) of 11nM and an EC(50) of 24nM, while its 3R,4S-isomer 20f-2 exhibited a K(i) of 8.6 and an IC(50) of 65nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 20f-1 also demonstrated efficacy in diet-induced obese rats.
Assuntos
Pirrolidinas/síntese química , Receptor Tipo 4 de Melanocortina/agonistas , Animais , Disponibilidade Biológica , Humanos , Injeções Intravenosas , Ligação Proteica/fisiologia , Pirrolidinas/administração & dosagem , Pirrolidinas/metabolismo , Ratos , Ratos Zucker , Receptor Tipo 4 de Melanocortina/metabolismoRESUMO
Divergent total syntheses of (+)-spegazzinine (1) and (-)-aspidospermine (2) and their extensions to the synthesis of C19-epi-aspidospermine and C3-epi-spegazzinine are detailed, confirming the relative stereochemistry and establishing the absolute configuration of (+)-spegazzinine. A powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole provided the pentacyclic skeleton and all the requisite stereochemistry of the natural products in a single reaction that forms three rings, four C-C bonds, and five stereocenters.
Assuntos
Alcaloides/síntese química , Alcaloides Indólicos/síntese química , Quinolinas/síntese química , Alcaloides/química , Ciclização , Alcaloides Indólicos/química , Estrutura Molecular , Oxidiazóis/química , Quinolinas/química , EstereoisomerismoRESUMO
A series of pyrrolidine derivatives were synthesized and characterized as potent agonists of the human melanocortin-4 receptor. For example, 28c had a K(i) of 13 nM in binding affinity and EC(50) of 6.9 nM in agonist potency with an intrinsic activity of 100% of the endogenous ligand alpha-MSH.
Assuntos
Pirrolidinas/farmacologia , Receptor Tipo 4 de Melanocortina/agonistas , Linhagem Celular , HumanosRESUMO
A series of pyrrolidinones derived from phenylalanines were synthesized as potent antagonists of the human melanocortin-4 receptor. These compounds showed high potencies and selectivities, and several of them had good oral bioavailabilities. In addition, 12e demonstrated in vivo efficacy in a murine cachexia model.
Assuntos
Caquexia/tratamento farmacológico , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Composição Corporal , Peso Corporal , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Pirrolidinonas/administração & dosagem , Pirrolidinonas/uso terapêutico , Relação Estrutura-AtividadeRESUMO
A series of pyrrolidinones derived from phenylalaninepiperazines were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor. In addition to their high binding affinities, these compounds displayed high functional potencies. 12a had a K(i) of 0.94 nM in binding and IC(50) of 21 nM in functional activity. 12a also demonstrated efficacy in a mouse cachexia model.
Assuntos
Pirrolidinonas/química , Pirrolidinonas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Receptor Tipo 4 de Melanocortina/metabolismo , Alquilação , Aminas/química , Animais , Encéfalo/efeitos dos fármacos , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Pirrolidinonas/síntese química , Pirrolidinonas/farmacocinética , Relação Estrutura-AtividadeRESUMO
A series of 3-arylpropionylpiperazines were synthesized as antagonists of the melanocortin-4 receptor. Their potency was found to be increased by replacing the alpha-methyl substituent of the initial lead 11 with a larger s-Bu or i-Bu group. Further potency enhancement was observed when a glycine or beta-alanine was incorporated onto the benzylamine. Some compounds demonstrated good potency, moderate selectivity, and oral bioavailability.
Assuntos
Piperazinas/química , Piperazinas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Animais , Benzilaminas/química , Humanos , Camundongos , Estrutura Molecular , Piperazina , Piperazinas/síntese química , Piperazinas/farmacocinética , Receptor Tipo 4 de Melanocortina/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 2-pyridinylpiperazines derived from beta-Ala-(2,4-Cl)Phe dipeptide was synthesized for the study of their SARs and possible interactions with the MC4 receptor. Compounds such as 11k (Ki=6.5 nM) possessed high potency.
Assuntos
Piperazinas/síntese química , Piperazinas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Dipeptídeos/química , Desenho de Fármacos , Humanos , Relação Estrutura-Atividade , beta-Alanina/químicaRESUMO
A series of alpha-benzylpropionylpiperazines were synthesized and tested as antagonists of the melanocortin-4 receptor. In addition to its high potency and selectivity, R-11a had desirable pharmacokinetic properties including high brain penetration in mice.
Assuntos
Piperazinas/química , Piperazinas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Receptor Tipo 4 de Melanocortina/metabolismo , Amidas/química , Animais , Humanos , Ligantes , Camundongos , Estrutura Molecular , Piperazina , Piperazinas/síntese química , Piperazinas/farmacocinética , Relação Estrutura-AtividadeRESUMO
[reaction: see text] 2-[4-(tert-Butoxycarbonyl)piperazinyl]benzylidene-tert-butanesulfinamides underwent nucleophilic 1,2-addition with different organometallic reagents to give highly diastereomerically enriched adducts. X-ray crystallography of the resulting alpha-branched N-Boc-2-piperazinylbenzyl-tert-butanesulfinamides confirms different mechanisms depending on the organometallic reagent used. Differential deprotection of the N-Boc and the tert-butanesulfinamides was investigated, and the dehydration byproducts have been identified and characterized. To avoid the formation of byproducts in the acidic deprotection step, the N-tert-butanesulfinamide group was converted to the corresponding N-tert-butanesulfonamide (Bus), which allowed for clean orthogonal deprotection. The efficient synthesis and deprotection of the N-Boc-2-piperazinylbenzyl-tert-butanesulfinamides herein described constitutes an attractive method for extensive structure-activity studies in the search for novel ligands of the human melanocortin 4 receptor.
Assuntos
Benzilaminas/química , Butanos/química , Iminas/química , Enxofre/química , Aldeídos/química , Alquilação , Carbono/química , Catálise , Cristalografia por Raios X , Iminas/síntese química , Lítio/química , Estrutura Molecular , Nitrogênio/química , EstereoisomerismoRESUMO
The melanocortin-4 receptor (MC4R) plays an important role in the regulation of energy homeostasis. Recent studies have shown that blockade of the MC4R reverses tumor-induced weight loss in mice. Herein, we describe the synthesis and identification of potent and selective non-peptide antagonists of the human MC4R from a series of 2-ethoxycarbonylcyclohexyl-piperazines. Compound 12i was found to possess low nanomolar affinity for the MC4R, and exhibit oral bioavailability in rats. More importantly, when administered orally to mice (10 mg/kg), it led to statistically significant increases in food intake over a 24-h period.
Assuntos
Piperazinas/síntese química , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Caquexia/tratamento farmacológico , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ligação Proteica , Ratos , Relação Estrutura-AtividadeRESUMO
Full details of a convergent total synthesis of the ramoplanin A2 and ramoplanose aglycon are disclosed. Three key subunits composed of residues 3-9 (heptapeptide 15), pentadepsipeptide 26 (residues 1, 2 and 15-17), and pentapeptide 34 (residues 10-14) were prepared, sequentially coupled, and cyclized to provide the 49-membered depsipeptide core of the aglycon. Key to the preparation of the pentadepsipeptide 26 incorporating the backbone ester was the asymmetric synthesis of an orthogonally protected l-threo-beta-hydroxyasparagine and the development of effective and near-racemization free conditions for esterification of its hindered alcohol (EDCI, DMAP, 0 degrees C). The coupling sites were chosen to maximize the convergency of the synthesis including that of the three subunits, to prevent late stage racemization of carboxylate-activated phenylglycine-derived residues, and to enlist beta-sheet preorganization of an acyclic macrocyclization substrate for 49-membered ring closure. By altering the order of final couplings, two macrocyclization sites, Phe(9)-d-Orn(10) and Gly(14)-Leu(15), were examined. Macrocyclization at the highly successful Phe(9)-d-Orn(10) site (89%) may benefit from both beta-sheet preorganization as well as closure at a d-amine terminus within the confines of a beta-turn at the end of the H-bonded antiparallel beta-strands. A more modest, but acceptable macrocyclization reaction at the Gly(14)-Leu(15) site (40-50%) found at the other end of the H-bonded antiparallel beta-strands within a small flexible loop may also benefit from preorganization of the cyclization substrate, is conducted on a substrate incapable of competitive racemization, and accommodates the convergent preparation of analogues bearing depsipeptide modifications. Deliberate late-stage incorporation of the subunit bearing the labile depsipeptide ester and a final stage Asn(1) side-chain introduction provides future access to analogues of the aglycons which themselves are equally potent or more potent than the natural products in antimicrobial assays.