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1.
Bioorg Med Chem Lett ; 28(3): 310-314, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29292229

RESUMO

This article describes our work towards the identification of a potent and selective inhibitor of mouse chitotriosidase (mCHIT1). A series of small molecule inhibitors of mCHIT1 and mAMCase have been developed from early lead compound 1. Examination of synthetized analogues led to discovery of several novel highly potent compounds. Among them compound 9 (OAT-2068) displays a remarkable 143-fold mCHIT1 vs. mAMCase selectivity. To explain the observed SAR molecular docking experiments were performed, which were in line with the experimental data from the enzymatic assays. Inhibitor 9 (OAT-2068) was found to have an excellent pharmacokinetic profile. This, together with high activity and selectivity, makes the compound an ideal and unique tool for studying the role of CHIT1 in biological models.


Assuntos
Descoberta de Drogas , Hexosaminidases/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Hexosaminidases/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
2.
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
3.
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
4.
ACS Med Chem Lett ; 11(6): 1228-1235, 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32551005

RESUMO

Human acidic mammalian chitinase (hAMCase) is one of two true chitinases in humans, the function of which remains elusive. In addition to the defense against highly antigenic chitin and chitin-containing pathogens in the gastric and intestinal contents, AMCase has been implicated in asthma, allergic inflammation, and ocular pathologies. Potent and selective small-molecule inhibitors of this enzyme have not been identified to date. Here we describe structural modifications of compound OAT-177, a previously developed inhibitor of mouse AMCase, leading to OAT-1441, which displays high activity and selectivity toward hAMCase. Significantly reduced off-target activity toward the human ether-à-go-go-related gene (hERG) and a good pharmacokinetic profile make OAT-1441 a potential candidate for further preclinical development as well as a useful tool compound to study the physiological role of hAMCase.

5.
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
6.
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
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