RESUMO
Adenosine suppresses antitumor immune responses via A2a and A2b receptors expressed on intratumoral immune cells. This effect is mediated by increased cyclic adenosine 5'-monophosphate (AMP) levels and phosphorylation of cyclic AMP response element binding protein (CREB). We conducted a phase 1, placebo-controlled, single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study to assess the safety, tolerability, pharmacokinetics (PK), including food effect (FE), and pharmacodynamics (PD) of oral AB928, a novel dual A2aR/A2bR antagonist, in healthy volunteers. AB928 doses between 10 and 200 mg once daily and 100 mg twice daily were evaluated. The study enrolled 85 subjects (randomized 3:1, AB928:placebo), 40 each in the SAD and MAD cohorts, and 5 in the FE cohort. AB928 was well tolerated up to the highest dose tested and did not affect any physiologic parameters potentially sensitive to adenosine inhibition. No safety concern was identified. The PK profile of AB928 was linear and dose-proportional, and a clear PK/PD correlation was demonstrated. Significant inhibition of adenosine receptor-mediated phosphorylated CREB was observed at peak plasma concentrations in all dose cohorts and at trough plasma concentrations in the higher-dose cohorts. AB928 plasma levels ≥1 µM were associated with ≥90% adenosine receptor inhibition. In the postprandial state, the rate of AB928 absorption decreased but the extent of absorption was unchanged. Together, these data support further clinical development of oral AB928 in cancer patients.
Assuntos
Antagonistas de Receptores Purinérgicos P1/administração & dosagem , Administração Oral , Adolescente , Adulto , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Método Duplo-Cego , Feminino , Interações Alimento-Droga , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores Purinérgicos P1/sangue , Antagonistas de Receptores Purinérgicos P1/farmacocinética , Adulto JovemRESUMO
In this Letter, we report the continued optimization of the N-acyl-2-aminobenzimidazole series, focusing in particular on the N-alkyl substituent and 5-position of the benzimidazole based on the binding mode and the early SAR. These efforts led to the discovery of 16, a highly potent, selective, and orally bioavailable inhibitor of IRAK-4.
Assuntos
Descoberta de Drogas , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Benzimidazóis/química , Ativação Enzimática/efeitos dos fármacos , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Ratos , Relação Estrutura-AtividadeRESUMO
While it has long been established that the chemokine receptor CCR9 and its ligand CCL25 are essential for the movement of leukocytes into the small intestine and the development of small-intestinal inflammation, the role of this chemokine-receptor pair in colonic inflammation is not clear. Toward this end, we compared colonic CCL25 protein levels in healthy individuals to those in patients with ulcerative colitis. In addition, we determined the effect of CCR9 pharmacological inhibition in the mdr1a(-/-) mouse model of ulcerative colitis. Colon samples from patients with ulcerative colitis had significantly higher levels of CCL25 protein compared to healthy controls, a finding mirrored in the mdr1a(-/-) mice. In the mdr1a(-/-) mice, CCR9 antagonists significantly decreased the extent of wasting and colonic remodeling and reduced the levels of inflammatory cytokines in the colon. These findings indicate that the CCR9:CCL25 pair plays a causative role in ulcerative colitis and suggest that CCR9 antagonists will provide a therapeutic benefit in patients with colonic inflammation.
Assuntos
Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Receptores CCR/antagonistas & inibidores , Receptores CCR/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Quimiocinas CC/genética , Quimiocinas CC/metabolismo , Colite Ulcerativa/genética , Feminino , Humanos , Técnicas In Vitro , Camundongos , Camundongos Knockout , Sulfonamidas/uso terapêuticoRESUMO
Necrotizing and crescentic GN (NCGN) with a paucity of glomerular immunoglobulin deposits is associated with ANCA. The most common ANCA target antigens are myeloperoxidase (MPO) and proteinase 3. In a manner that requires activation of the alternative complement pathway, passive transfer of antibodies to mouse MPO (anti-MPO) induces a mouse model of ANCA NCGN that closely mimics human disease. Here, we confirm the importance of C5aR/CD88 in the mediation of anti-MPO-induced NCGN and report that C6 is not required. We further demonstrate that deficiency of C5a-like receptor (C5L2) has the reverse effect of C5aR/CD88 deficiency and results in more severe disease, indicating that C5aR/CD88 engagement enhances inflammation and C5L2 engagement suppresses inflammation. Oral administration of CCX168, a small molecule antagonist of human C5aR/CD88, ameliorated anti-MPO-induced NCGN in mice expressing human C5aR/CD88. These observations suggest that blockade of C5aR/CD88 might have therapeutic benefit in patients with ANCA-associated vasculitis and GN.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/prevenção & controle , Autoantígenos/imunologia , Glomerulonefrite/prevenção & controle , Peroxidase/imunologia , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Administração Oral , Animais , Complemento C6/imunologia , Via Alternativa do Complemento , Relação Dose-Resposta a Droga , Técnicas de Introdução de Genes , Glomerulonefrite/complicações , Glomerulonefrite/imunologia , Hematúria/etiologia , Hematúria/prevenção & controle , Humanos , Imunização Passiva , Leucócitos , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/imunologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peroxidase/deficiência , Proteinúria/etiologia , Proteinúria/prevenção & controle , Receptor da Anafilatoxina C5a/deficiência , Receptor da Anafilatoxina C5a/genética , Receptores de Quimiocinas/deficiência , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/fisiologia , Proteínas Recombinantes de Fusão , Urina/citologiaRESUMO
The chemokine CCL3/MIP-1α is a risk factor in the outcome of multiple myeloma (MM), particularly in the development of osteolytic bone disease. This chemokine, highly overexpressed by MM cells, can signal mainly through 2 receptors, CCR1 and CCR5, only 1 of which (CCR1) is responsive to CCL3 in human and mouse osteoclast precursors. CCR1 activation leads to the formation of osteolytic lesions and facilitates tumor growth. Here we show that formation of mature osteoclasts is blocked by the highly potent and selective CCR1 antagonist CCX721, an analog of the clinical compound CCX354. We also show that doses of CCX721 selected to completely inhibit CCR1 produce a profound decrease in tumor burden and osteolytic damage in the murine 5TGM1 model of MM bone disease. Similar effects were observed when the antagonist was used prophylactically or therapeutically, with comparable efficacy to that of zoledronic acid. 5TGM1 cells were shown to express minimal levels of CCR1 while secreting high levels of CCL3, suggesting that the therapeutic effects of CCX721 result from CCR1 inhibition on non-MM cells, most likely osteoclasts and osteoclast precursors. These results provide a strong rationale for further development of CCR1 antagonists for the treatment of MM and associated osteolytic bone disease.
Assuntos
Quimiocinas/farmacologia , Quimiocinas/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Osteólise/tratamento farmacológico , Receptores CCR1/antagonistas & inibidores , Carga Tumoral/efeitos dos fármacos , Administração Oral , Animais , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , Quimiocinas/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Imunocompetência/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Mieloma Múltiplo/complicações , Mieloma Múltiplo/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteólise/complicações , Osteólise/patologia , Ratos , Receptores CCR1/metabolismoRESUMO
A novel series of benzenesulfonanilide derivatives of 11ß-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitro biological evaluation, and structure-activity relationship of these compounds are presented. Optimization of this series rapidly resulted in the discovery of compounds (S)-10 and (S)-23 (11ß-HSD1 SPA IC(50)=1.8 and 1.4 nM, respectively).
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Anilidas/química , Compostos de Anilina/química , Inibidores Enzimáticos/química , Piperazinas/química , Sulfonamidas/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/farmacologia , Anilidas/síntese química , Compostos de Anilina/síntese química , Compostos de Anilina/farmacologia , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Células HEK293 , Humanos , Conformação Molecular , Piperazina , Piperazinas/síntese química , Piperazinas/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , TransfecçãoRESUMO
T cells play a critical role in the control of cancer. The development of immune checkpoint blockers (ICB) aimed at enhancing antitumor T-cell responses has revolutionized cancer treatment. However, durable clinical benefit is observed in only a subset of patients, prompting research efforts to focus on strategies that target multiple inhibitory signals within the tumor microenvironment (TME) to limit tumor evasion and improve patient outcomes. Adenosine has emerged as a potent immune suppressant within the TME, and CD73 is the major enzyme responsible for its extracellular production. CD73 can be co-opted within the TME to impair T-cell-mediated antitumor immunity and promote tumor growth. To target this pathway and block the formation of adenosine, we designed a novel, selective, and potent class of small-molecule inhibitors of CD73, including AB680 (quemliclustat), which is currently being tested in patients with cancer. AB680 effectively restored T-cell proliferation, cytokine secretion, and cytotoxicity that were dampened by the formation of immunosuppressive adenosine by CD73. Furthermore, in an allogeneic mixed lymphocyte reaction where CD73-derived adenosine had a dominant suppressive effect in the presence of PD-1 blockade, AB680 restored T-cell activation and function. Finally, in a preclinical mouse model of melanoma, AB680 inhibited CD73 in the TME and increased the antitumor activity of PD-1 blockade. Collectively, these data provide a rationale for the inhibition of CD73 with AB680 in combination with ICB, such as anti-PD-1, to improve cancer patient outcomes.
Assuntos
Melanoma , Receptor de Morte Celular Programada 1 , Adenosina/metabolismo , Adenosina/farmacologia , Adenosina/uso terapêutico , Animais , Humanos , Inibidores de Checkpoint Imunológico , Melanoma/tratamento farmacológico , Camundongos , Receptor de Morte Celular Programada 1/metabolismo , Microambiente TumoralRESUMO
Phosphoinositide-3-kinase γ (PI3Kγ) is highly expressed in immune cells and promotes the production and migration of inflammatory mediators. The inhibition of PI3Kγ has been shown to repolarize the tumor immune microenvironment to a more inflammatory phenotype, thereby controlling immune suppression in cancer. Herein, we report the structure-based optimization of an early lead series of pyrazolopyrimidine isoindolinones, which culminated in the discovery of highly potent and isoform-selective PI3Kγ inhibitors with favorable drug-like properties. X-ray cocrystal structure analysis, molecular docking studies, and detailed structure-activity relationship investigations resulted in the identification of the optimal amide and isoindolinone substituents to achieve a desirable combination of potency, selectivity, and metabolic stability. Preliminary in vitro studies indicate that inhibition of PI3Kγ with compound 56 results in a significant immune response by increasing pro-inflammatory cytokine gene expression in M1 macrophages.
Assuntos
Amidas/química , Classe Ib de Fosfatidilinositol 3-Quinase/química , Desenho de Fármacos , Descoberta de Drogas , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Pirimidinas/química , Animais , Humanos , Masculino , Simulação de Acoplamento Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
The synthesis and SAR of a series of 4,4-disubstituted cyclohexylbenzamide inhibitors of 11ß-HSD1 are described. Optimization rapidly led to potent, highly selective, and orally bioavailable inhibitors demonstrating efficacy in both rat and non-human primate ex vivo pharmacodynamic models.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Benzamidas/química , Inibidores Enzimáticos/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Administração Oral , Animais , Benzamidas/síntese química , Benzamidas/farmacocinética , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Macaca fascicularis , Microssomos Hepáticos/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
A bis-amide antagonist of Smoothened, a seven-transmembrane receptor in the Hedgehog signaling pathway, was discovered via high throughput screening. In vitro and in vivo experiments demonstrated that the bis-amide was susceptible to N-acyl transferase mediated amide scission. Several bioisosteric replacements of the labile amide that maintained in vitro potency were identified and shown to be metabolically stable in vitro and in vivo.
Assuntos
Aciltransferases/antagonistas & inibidores , Amidas/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Aciltransferases/metabolismo , Amidas/química , Amidas/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Ensaios de Triagem em Larga Escala , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Solid tumors are often associated with high levels of extracellular ATP. Ectonucleotidases catalyze the sequential hydrolysis of ATP to adenosine, which potently suppresses T-cell and NK-cell functions via the adenosine receptors (A2a and A2b). The ectonucleotidase CD73 catalyzes the conversion of AMP to adenosine. Thus, increased CD73 enzymatic activity in the tumor microenvironment is a potential mechanism for tumor immune evasion and has been associated with poor prognosis in the clinic. CD73 inhibition is anticipated to restore immune function by skirting this major mechanism of adenosine generation. We have developed a series of potent and selective methylenephosphonic acid CD73 inhibitors via a structure-based design. Key binding interactions of the known inhibitor adenosine-5'-(α,ß-methylene)diphosphate (AMPCP) with hCD73 provided the foundation for our early designs. The structure-activity relationship study guided by this structure-based design led to the discovery of 4a, which exhibits excellent potency against CD73, exquisite selectivity against related ectonucleotidases, and a favorable pharmacokinetic profile.
Assuntos
5'-Nucleotidase/antagonistas & inibidores , Ácidos Fosforosos/química , 5'-Nucleotidase/genética , 5'-Nucleotidase/metabolismo , Adenosina/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Humanos , Simulação de Dinâmica Molecular , Ácidos Fosforosos/metabolismo , Relação Estrutura-AtividadeRESUMO
The Hedgehog (Hh) signaling pathway regulates cell proliferation and differentiation in developing tissues, and abnormal activation of the Hh pathway has been linked to several tumor subsets. As a transducer of Hh signaling, the GPCR-like protein Smoothened (Smo) is a promising target for disruption of unregulated Hh signaling. A series of 1-amino-4-arylphthalazines was developed as potent and orally bioavailable inhibitors of Smo. A representative compound from this class demonstrated significant tumor volume reduction in a mouse medulloblastoma model.
Assuntos
Ftalazinas/química , Ftalazinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Desenho de Fármacos , Proteínas Hedgehog , Humanos , Meduloblastoma/tratamento farmacológico , Meduloblastoma/patologia , Camundongos , Ftalazinas/síntese química , Transdução de Sinais , Receptor SmoothenedRESUMO
In this communication, human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitory activities of a novel series of diarylsulfones are described. Optimization of this series resulted in several highly potent 11ß-HSD1 inhibitors with excellent pharmacokinetic (PK) properties. Compound (S)-25 showed excellent efficacy in a non-human primate ex vivo pharmacodynamic model.
Assuntos
Inibidores Enzimáticos/síntese química , Sulfonas/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Farmacocinética , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacocinéticaRESUMO
In the tumor microenvironment, unusually high concentrations of extracellular adenosine promote tumor proliferation through various immunosuppressive mechanisms. Blocking adenosine production by inhibiting nucleotide-metabolizing enzymes, such as ectonucleotidases CD73 and CD39, represents a promising therapeutic strategy that may synergize with other immuno-oncology mechanisms and chemotherapies. Emerging small-molecule ectonucleotidase inhibitors have recently entered clinical trials. This Perspective will outline challenges, strategies, and recent advancements in targeting this class with small-molecule inhibitors, including AB680, the first small-molecule CD73 inhibitor to enter clinical development. Specific case studies, including structure-based drug design and lead optimization, will be outlined. Preclinical data on these molecules and their ability to enhance antitumor immunity will be discussed.
Assuntos
5'-Nucleotidase/metabolismo , Apirase/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Inibidores Enzimáticos/metabolismo , Nucleotídeos/metabolismo , 5'-Nucleotidase/antagonistas & inibidores , 5'-Nucleotidase/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/metabolismo , Apirase/antagonistas & inibidores , Apirase/química , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/química , Proteínas Ligadas por GPI/metabolismo , Humanos , Nucleotídeos/antagonistas & inibidores , Nucleotídeos/química , Estrutura Secundária de ProteínaRESUMO
CD73 is an extracellular mediator of purinergic signaling. When upregulated in the tumor microenvironment, CD73 has been implicated in the inhibition of immune function through overproduction of adenosine. Traditional efforts to inhibit CD73 have involved antibody therapy or the development of small molecules, the most potent of which mimic the acidic and ionizable structure of the enzyme's natural substrate, adenosine 5'-monophosphate (AMP). Here, we report the systematic discovery of a novel class of non-nucleotide CD73 inhibitors that are more potent than all other nonphosphonate inhibitor classes reported to date. These efforts have culminated in the discovery of 4-({5-[4-fluoro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (73, IC50 = 12 nM) and 4-({5-[4-chloro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (74, IC50 = 19 nM). Cocrystallization of 74 with human CD73 demonstrates a competitive binding mode. These compounds show promise for the improvement of drug-like character via the attenuation of the acidity and low membrane permeability inherent to known nucleoside inhibitors of CD73.
Assuntos
5'-Nucleotidase/antagonistas & inibidores , Descoberta de Drogas/métodos , Triazóis/química , Triazóis/farmacologia , 5'-Nucleotidase/metabolismo , Animais , Ligação Competitiva/efeitos dos fármacos , Ligação Competitiva/fisiologia , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Cristalografia por Raios X/métodos , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , HumanosRESUMO
Extracellular adenosine (ADO), present in high concentrations in the tumor microenvironment (TME), suppresses immune function via inhibition of T cell and NK cell activation. Intratumoral generation of ADO depends on the sequential catabolism of ATP by two ecto-nucleotidases, CD39 (ATP â AMP) and CD73 (AMP â ADO). Inhibition of CD73 eliminates a major pathway of ADO production in the TME and can reverse ADO-mediated immune suppression. Extensive interrogation of structure-activity relationships (SARs), structure-based drug design, and optimization of pharmacokinetic properties culminated in the discovery of AB680, a highly potent (Ki = 5 pM), reversible, and selective inhibitor of CD73. AB680 is further characterized by very low clearance and long half-lives across preclinical species, resulting in a PK profile suitable for long-acting parenteral administration. AB680 is currently being evaluated in phase 1 clinical trials. Initial data show AB680 is well tolerated and exhibits a pharmacokinetic profile suitable for biweekly (Q2W) iv-administration in human.
Assuntos
5'-Nucleotidase/antagonistas & inibidores , Descoberta de Drogas/métodos , Bibliotecas de Moléculas Pequenas/síntese química , 5'-Nucleotidase/genética , Animais , Sítios de Ligação , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/genética , Haplorrinos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Camundongos , Modelos Moleculares , Ligação Proteica , Ratos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-AtividadeRESUMO
The successful application of immunotherapy in the treatment of cancer relies on effective engagement of immune cells in the tumor microenvironment. Phosphoinositide 3-kinase γ (PI3Kγ) is highly expressed in tumor-associated macrophages, and its expression levels are associated with tumor immunosuppression and growth. Selective inhibition of PI3Kγ offers a promising strategy in immuno-oncology, which has led to the development of numerous potent PI3Kγ inhibitors with variable selectivity profiles. To facilitate further investigation of the therapeutic potential of PI3Kγ inhibition, we required a potent and PI3Kγ-selective tool compound with sufficient metabolic stability for use in future in vivo studies. Herein, we describe some of our efforts to realize this goal through the systematic study of SARs within a series of 7-azaindole-based PI3Kγ inhibitors. The large volume of data generated from this study helped guide our subsequent lead optimization efforts and will inform further development of PI3Kγ-selective inhibitors for use in immunomodulation.
RESUMO
The selective inhibition of the lipid signaling enzyme PI3Kγ constitutes an opportunity to mediate immunosuppression and inflammation within the tumor microenvironment but is difficult to achieve due to the high sequence homology across the class I PI3K isoforms. Here, we describe the design of a novel series of potent PI3Kγ inhibitors that attain high isoform selectivity through the divergent projection of substituents into both the "selectivity" and "alkyl-induced" pockets within the adenosine triphosphate (ATP) binding site of PI3Kγ. These efforts have culminated in the discovery of 5-[2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-[(1S)-1-cyclopropylethyl]-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (4, IC50 = 0.064 µM, THP-1 cells), which displays >600-fold selectivity for PI3Kγ over the other class I isoforms and is a promising step toward the identification of a clinical development candidate. The structure-activity relationships identified throughout this campaign demonstrate that greater γ-selectivity can be achieved by inhibitors that occupy an "alkyl-induced" pocket and possess bicyclic hinge-binding motifs capable of forming more than one hydrogen bond to the hinge region of PI3Kγ.
Assuntos
Classe Ib de Fosfatidilinositol 3-Quinase/efeitos dos fármacos , Desenho de Fármacos , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Animais , Cristalografia por Raios X , Humanos , Simulação de Acoplamento Molecular , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Discovery and optimization of a piperidyl benzamide series of 11beta-HSD1 inhibitors is described. This series was derived from a cyclohexyl benzamide lead structures to address PXR selectivity, high non-specific protein binding, poor solubility, limited in vivo exposure, and in vitro cytotoxicity issues observed with the cyclohexyl benzamide structures. These efforts led to the discovery of piperidyl benzamide 15 which features improved properties over the cyclohexyl benzamide derivatives.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Benzamidas/síntese química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/metabolismo , Piperidinas/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , Benzamidas/farmacologia , Cristalografia por Raios X/métodos , Desenho de Fármacos , Hepatócitos/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Microssomos/metabolismo , Modelos Químicos , Estrutura Molecular , Solubilidade , Relação Estrutura-AtividadeRESUMO
The synthesis and SAR of a series of arylsulfonylpiperazine inhibitors of 11beta-HSD1 are described. Optimization rapidly led to potent, selective, and orally bioavailable inhibitors demonstrating efficacy in a cynomolgus monkey ex vivo enzyme inhibition model.