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1.
Bioorg Med Chem ; 25(16): 4265-4276, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28662964

RESUMO

Cyclolinopeptide A (CLA), an immunosuppressive nonapeptide derived from linen seeds, was modified with S or R-γ4-bis(homo-phenylalanine) in positions 3 or 4, or both 3 and 4. These modifications changed the flexibility of new analogues and distribution of intramolecular hydrogen bonds. Analogues 11 c(Pro1-Pro2-Phe3-S-γ4-hhPhe4-Leu5-Ile6-Ile7-Leu8-Val9), 13 c(Pro1-Pro2-S-γ4-hhPhe3-R-γ4-hhPhe4-Leu5-Ile6-Ile7-Leu8-Val9) and 15 c(Pro1-Pro2-R-γ4-hhPhe3-Phe4-Leu5-Ile6-Ile7-Leu8-Val9) existed as a mixture of stable cis/trans isomers of Pro-Pro peptide bond. The comparison of the relative spatial orientations in crystal state of the two carbonyl groups, neighboring γ-amino acids, revealed conformational similarities to α-peptides. The addition of two -CH2- groups in γ-amino acids led to a more rigid conformation, although a more flexible one was expected. A significant difference in the relative orientation of the carbonyl groups was found for cyclic γ-peptides with a dominance of an antiparallel arrangement. As carbonyl groups may be engaged in the interactions with plausible receptors through hydrogen bonds, a similar biological activity of the modified peptides was expected. Our biological studies showed that certain cyclic, but not the corresponding linear peptides, lowered the viability of peripheral blood mononuclear cells (PBMC) at 100µg/mL concentration. The proliferation of PBMC induced by phytohemagglutinin A (PHA) was strongly inhibited by cyclic peptides only, in a dose-dependant manner. On the other hand, lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α) production in whole blood cell cultures was inhibited by both linear and cyclic peptides. Peptide 15 c(Pro1-Pro2-R-γ4-hhPhe3-Phe4-Leu5-Ile6-Ile7-Leu8-Val9) blocked the expression of caspase-3, inhibited the expression of caspases-8 and -9 in 24h culture of Jurkat cells, and caused DNA fragmentation in these cells, as an indicator of apoptosis. Thus, we revealed a new mechanism of immunosuppressive action of a nonapeptide.


Assuntos
Aminobutiratos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Aminobutiratos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Células Jurkat , Lipopolissacarídeos/farmacologia , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Relação Estrutura-Atividade
2.
Acta Crystallogr Sect E Struct Rep Online ; 70(Pt 10): o1081-2, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25484683

RESUMO

The characteristic feature of the title mol-ecule, C16H23NO4, is the syn configuration of the partially double amide C-N bond [C-N-C-O torsion angle = -14.8 (2)°]. The crystal packing is determined by inter-molecular O-H⋯O and N-H⋯O hydrogen bonds, which link the mol-ecules into a double-chain structure extending along [010].

3.
Eur J Med Chem ; 264: 116033, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38096651

RESUMO

Arginase is a multifaced enzyme that plays an important role in health and disease being regarded as a therapeutic target for the treatment of various pathological states such as malignancies, asthma, and cardiovascular disease. The discovery of boronic acid-based arginase inhibitors in 1997 revolutionized attempts of medicinal chemistry focused on development of drugs targeting arginase. Unfortunately, these very polar compounds had limitations such as analysis and purification without chromophores, synthetically challenging space, and poor oral bioavailability. Herein, we present a novel class of boronic acid-based arginase inhibitors which are piperidine derivatives exhibiting a different pharmacological profile compared to our drug candidate in cancer immunotherapy -OATD-02 - dual ARG1/2 inhibitor with high intracellular activity. Compounds from this new series show low intracellular activity, hence they can inhibit mainly extracellular arginase, providing different therapeutic space compared to a dual intracellular ARG1/2 inhibitor. The disclosed series showed good inhibitory potential towards arginase enzyme in vitro (IC50 up to 160 nM), favorable pharmacokinetics in animal models, and encouraging preliminary in vitro and in vivo tolerability. Compounds from the new series have moderate-to-high oral bioavailability (up to 66 %) and moderate clearance in vivo. Herein we describe the development and optimization of the synthesis of the new class of boronic acid-based arginase inhibitors via a ring expansion approach starting from the inexpensive chirality source (d-hydroxyproline). This upgraded methodology facilitated a gram-scale delivery of the final compound and eliminated the need for costly and time-consuming chiral resolution.


Assuntos
Arginase , Inibidores Enzimáticos , Animais , Arginase/química , Inibidores Enzimáticos/química , Ácidos Borônicos/farmacologia , Hidroxiprolina , Química Farmacêutica
4.
J Med Chem ; 67(5): 3959-3985, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38427954

RESUMO

Chitinase-3-like-1 (CHI3L1), also known as YKL-40, is a glycoprotein linked to inflammation, fibrosis, and cancer. This study explored CHI3L1's interactions with various oligosaccharides using microscale thermophoresis (MST) and AlphaScreen (AS). These investigations guided the development of high-throughput screening assays to assess interference of small molecules in binding between CHI3L1 and biotinylated small molecules or heparan sulfate-based probes. Small molecule binders of YKL-40 were identified in our chitotriosidase inhibitors library with MST and confirmed through X-ray crystallography. Based on cocrystal structures of potent hit compounds with CHI3L1, small molecule probes 19 and 20 were designed for an AS assay. Structure-based optimization led to compounds 30 and 31 with nanomolar activities and drug-like properties. Additionally, an orthogonal AS assay using biotinylated heparan sulfate as a probe was developed. The compounds' affinity showed a significant correlation in both assays. These screening tools and compounds offer novel avenues for investigating the role of CHI3L1.


Assuntos
Quitinases , Proteína 1 Semelhante à Quitinase-3 , Glicoproteínas , Ensaios de Triagem em Larga Escala , Heparitina Sulfato
5.
Mol Cancer Ther ; 22(7): 807-817, 2023 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-36939275

RESUMO

Pharmacologic inhibition of the controlling immunity pathway enzymes arginases 1 and 2 (ARG1 and ARG2) is a promising strategy for cancer immunotherapy. Here, we report the discovery and development of OATD-02, an orally bioavailable, potent arginases inhibitor. The unique pharmacologic properties of OATD-02 are evidenced by targeting intracellular ARG1 and ARG2, as well as long drug-target residence time, moderate to high volume of distribution, and low clearance, which may jointly provide a weapon against arginase-related tumor immunosuppression and ARG2-dependent tumor cell growth. OATD-02 monotherapy had an antitumor effect in multiple tumor models and enhanced an efficacy of the other immunomodulators. Completed nonclinical studies and human pharmacokinetic predictions indicate a feasible therapeutic window and allow for proposing a dose range for the first-in-human clinical study in patients with cancer. SIGNIFICANCE: We have developed an orally available, small-molecule intracellular arginase 1 and 2 inhibitor as a potential enhancer in cancer immunotherapy. Because of its favorable pharmacologic properties shown in nonclinical studies, OATD-02 abolishes tumor immunosuppression induced by both arginases, making it a promising drug candidate entering clinical trials.


Assuntos
Arginase , Neoplasias , Humanos , Arginase/metabolismo , Neoplasias/tratamento farmacológico , Imunoterapia
6.
Cancers (Basel) ; 14(16)2022 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-36010962

RESUMO

BACKGROUND: Arginases play essential roles in metabolic pathways, determining the fitness of both immune and tumour cells. Along with the previously validated role of ARG1 in cancer, the particular significance of ARG2 as a therapeutic target has emerged as its levels correlate with malignant phenotype and poor prognosis. These observations unveil arginases, and specifically ARG2, as well-validated and promising therapeutic targets. OATD-02, a new boronic acid derivative, is the only dual inhibitor, which can address the benefits of pharmacological inhibition of arginase 1 and 2 in cancer. METHODS: The inhibitory activity of OATD-02 was determined using recombinant ARG1 and ARG2, as well as in a cellular system using primary hepatocytes and macrophages. In vivo antitumor activity was determined in syngeneic models of colorectal and kidney carcinomas (CT26 and Renca, respectively), as well as in an ARG2-dependent xenograft model of leukaemia (K562). RESULTS: OATD-02 was shown to be a potent dual (ARG1/ARG2) arginase inhibitor with a cellular activity necessary for targeting ARG2. Compared to a reference inhibitor with predominant extracellular activity towards ARG1, we have shown improved and statistically significant antitumor efficacy in the CT26 model and an immunomodulatory effect reflected by Treg inhibition in the Renca model. Importantly, OATD-02 had a superior activity when combined with other immunotherapeutics. Finally, OATD-02 effectively inhibited the proliferation of human K562 leukemic cells both in vitro and in vivo. CONCLUSIONS: OATD-02 is a potent small-molecule arginase inhibitor with optimal drug-like properties, including PK/PD profile. Excellent activity against intracellular ARG2 significantly distinguishes OATD-02 from other arginase inhibitors. OATD-02 represents a very promising drug candidate for the combined treatment of tumours, and is the only pharmacological tool that can effectively address the benefits of ARG1/ARG2 inhibition. OATD-02 will enter clinical trials in cancer patients in 2022.

7.
Peptides ; 132: 170365, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32622694

RESUMO

The synthesis of new analogues of cyclolinopeptide A (CLA) and their linear precursors modified with (R)- and (S)-4-methylpseudoproline in the Pro3-Pro4 fragment are presented. The peptides were tested in comparison with cyclosporine A (CsA) in concanavalin A (Con A) and pokeweed mitogen (PWM)-induced mouse splenocyte proliferation and in secondary humoral immune response in vitro to sheep erythrocytes (SRBC). Their effects on expression of selected signaling molecules in the Jurkat T cell line were also determined. In addition, the structural features of the peptides, applying nuclear magnetic resonance and circular dichroism, were analyzed. The results showed that only peptides 7 and 8 modified with (R)-4-methylpseudoproline residue (c(Leu1-Val2-(R)-(αMe)Ser(ΨPro)3-Pro4-Phe5-Phe6-Leu7-Ile8-Ile9) and c(Leu1-Val2-Pro3-(R)-(αMe)Ser(ΨPro)4-Phe5-Phe6-Leu7-Ile8-Ile9), respectively) strongly suppressed mitogen-induced splenocyte proliferation and the humoral immune response, with peptide 8 being more potent. Likewise, peptide 8 more strongly elevated expression of Fas, a proapoptotic signaling molecule in Jurkat cells. We postulate that the increased biological activity of peptide 8, compared to the parent molecule and other studied peptides, resulted from its more flexible structure, found on the basis of both CD and NMR studies. CD and NMR spectra showed that replacement of Pro3 by (R)-(αMe)Ser(¬Pro) caused much greater conformational changes than the same replacement of the Pro4 residue. Such a modification could lead to increased conformational freedom of peptide 8, resulting in a greater ability to adopt a more compact structure, better suited to its putative receptor. In conclusion, peptide 8 is a potent immune suppressor which may find application in controlling immune disorders.


Assuntos
Doenças do Sistema Imunitário/tratamento farmacológico , Imunossupressores/química , Imunossupressores/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Prolina/análogos & derivados , Tiazóis/química , Tiazóis/farmacologia , Sequência de Aminoácidos , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Dicroísmo Circular/métodos , Feminino , Humanos , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/metabolismo , Imunossupressores/síntese química , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Camundongos , Camundongos Endogâmicos CBA , Peptídeos Cíclicos/síntese química , Prolina/síntese química , Prolina/química , Prolina/farmacologia , Ovinos , Baço/citologia , Baço/efeitos dos fármacos , Relação Estrutura-Atividade , Tiazóis/síntese química
8.
J Med Chem ; 63(24): 15527-15540, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33078933

RESUMO

Chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) are the enzymatically active chitinases that have been implicated in the pathology of chronic lung diseases such as asthma and interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis. The clinical and preclinical data suggest that pharmacological inhibition of CHIT1 might represent a novel therapeutic approach in IPF. Structural modification of an advanced lead molecule 3 led to the identification of compound 9 (OATD-01), a highly active CHIT1 inhibitor with both an excellent PK profile in multiple species and selectivity against a panel of other off-targets. OATD-01 given orally once daily in a range of doses between 30 and 100 mg/kg showed significant antifibrotic efficacy in an animal model of bleomycin-induced pulmonary fibrosis. OATD-01 is the first-in-class CHIT1 inhibitor, currently completed phase 1b of clinical trials, to be a potential treatment for IPF.


Assuntos
Quitinases/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Piperidinas/química , Administração Oral , Animais , Sítios de Ligação , Bleomicina/toxicidade , Domínio Catalítico , Quitinases/metabolismo , Ensaios Clínicos Fase I como Assunto , Modelos Animais de Doenças , Cães , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Feminino , Meia-Vida , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/patologia , Pulmão/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Ratos , Relação Estrutura-Atividade
9.
J Med Chem ; 62(15): 7126-7145, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31291098

RESUMO

Acidic mammalian chitinase (AMCase) and chitotriosidase-1 (CHIT1) are two enzymatically active proteins produced by mammals capable of cleaving the glycosidic bond in chitin. Based on the clinical findings and animal model studies, involvement of chitinases has been suggested in several respiratory system diseases including asthma, COPD, and idiopathic pulmonary fibrosis. Exploration of structure-activity relationships within the series of 1-(3-amino-1H-1,2,4-triazol-5-yl)-piperidin-4-amines, which was earlier identified as a scaffold of potent AMCase inhibitors, led us to discover highly active dual (i.e., AMCase and CHIT1) inhibitors with very good pharmacokinetic properties. Among them, compound 30 was shown to reduce the total number of cells in bronchoalveolar lavage fluid of mice challenged with house dust mite extract after oral administration (50 mg/kg, qd). In addition, affinity toward the hERG potassium channel of compound 30 was significantly reduced when compared to the earlier reported chitinase inhibitors.


Assuntos
Quitinases/antagonistas & inibidores , Quitinases/metabolismo , Desenvolvimento de Medicamentos/métodos , Doenças Respiratórias/enzimologia , Animais , Líquido da Lavagem Broncoalveolar , Células CHO , Cricetinae , Cricetulus , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-Dawley , Doenças Respiratórias/tratamento farmacológico , Resultado do Tratamento
10.
Eur J Med Chem ; 86: 515-27, 2014 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-25203781

RESUMO

Cyclolinopeptide A, naturally occurring immunomodulatory nonapeptide, was modified with S or R-γ(3)-bis(homophenylalanine) in positions 3 or 4, or both 3 and 4. The replacement of one or both Phe residues by γ(3)-hhPhe led to decrease of their conformational flexibility in the analogues in comparison to CLA. All cyclic peptides, except 11, exist as isomers with the cis Pro-Pro peptide bond. Cyclic peptide 11 with single modification S-γ(3)-hhPhe(4) exists as a mixture of two isomers and the major isomer (89%) contains all peptide bonds of the trans geometry. The peptides were subjected to several immunological tests in vitro and in vivo. Linear peptides 1-8, precursors of CLA analogues 9-16, were not toxic against human peripheral blood mononuclear cells (PBMC) but cyclic analogues showed dose-dependent toxicity with exception of peptide 11. Linear peptides did not inhibit mitogen-induced PBMC proliferation whereas cyclic ones inhibited the proliferation in a dose-dependent manner. The actions of linear and cyclic peptides with regard to lipopolysaccharide (LPS) -induced tumour necrosis factor alpha (TNF α) production in whole human blood cultures were differential but particularly suppressive in the case of linear compound 6. Therefore, for in vivo tests compounds 6 and 11 were selected. The compounds showed comparable, suppressive actions in induction and effector phases of delayed type hypersensitivity as well as in the carrageenan-induced foot pad edema in mouse models. In summary, linear peptide 6 and cyclic peptide 11 are attractive as potential immune suppressor drugs.


Assuntos
Terapia de Imunossupressão , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Fenilalanina/análogos & derivados , Animais , Carragenina , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/imunologia , Feminino , Humanos , Hipersensibilidade Tardia/imunologia , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Masculino , Camundongos , Camundongos Endogâmicos CBA , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/imunologia , Fenilalanina/química , Relação Estrutura-Atividade
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