RESUMO
Phosphoinositide 3-kinase (PI3K) pathway mediates key signaling events downstream to B-cell receptor (BCR) for survival of mature B-cells, and overexpression or overactivation of PI3Kδ is crucial for B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL). Small molecule PI3Kδγ inhibitors, with a known potential to reduce activated B-cell (ABC)-DLBCL transformation, form an important class of therapeutics approved for follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL). In this study, we describe discovery of a potent, selective and efficacious dual PI3Kδγ inhibitor, LL-00084282, having a differentiated efficacy profile in human ABC- and germinal center B-cell (GCB)-DLBCL cell lines. LL-00084282 displayed high potency and superior PI3Kδγ engagement with excellent selectivity over other PI3K isoforms at both IC50/90 concentrations in biochemical and cell-based assays. In contrast to selective PI3Kδ inhibitors, LL-00084282 showed superior and potent anticancer activity in both ABC- and GCB-DLBCL cell lines. LL-00084282 demonstrated in-vivo efficacy in OCI-Ly10 and SU-DHL-6 xenografts with good tolerability. Furthermore, LL-00084282 inhibited pro-inflammatory cytokine secretion and reduced basophil activation in human PBMCs, showing potential implications in immunoinflammatory conditions. Good pharmacokinetic properties in higher species and desirable efficacy profile highlights potential of this novel PI3Kδγ inhibitor for further clinical evaluation in DLBCL patients.
Assuntos
Leucemia Linfocítica Crônica de Células B , Linfoma Difuso de Grandes Células B , Inibidores de Fosfoinositídeo-3 Quinase , Humanos , Linfócitos B , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Fosfatidilinositol 3-Quinases , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Linhagem Celular TumoralRESUMO
The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.
Assuntos
Antineoplásicos/química , Naftiridinas/química , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/química , Quinolonas/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Naftiridinas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Quinolonas/metabolismo , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
The calcium sensing receptor (CaSR) plays an important role in maintaining calcium homeostasis. The use of calcimimetic cinacalcet has been established to activate CaSR and normalize hypercalcemia. However, cinacalcet has limitations due to its high cLogP and pKa. A systematic optimization of cinacalcet to reduce its cLogP and pKa yielded compound 23a (LNP1892). Compound 23a showed excellent potency and a favorable pharmacokinetics profile, and lacked the liabilities of cinacalcet, making it a highly differentiated precision calcimimetic. In adenine-diet-induced chronic kidney disease (CKD) models, 23a demonstrated robust and dose-dependent efficacy, as measured by plasma parathyroid hormone (PTH) levels. It also showed an excellent safety profile in animal studies. Phase 1 clinical trials with 23a in healthy volunteers confirmed its excellent safety, tolerability, and effectiveness in lowering PTH levels in a dose-dependent manner, without causing symptomatic hypocalcaemia. Encouraged by these promising results, LNP1892 was taken to a Phase 2 study in CKD patients.
Assuntos
Hiperparatireoidismo Secundário , Insuficiência Renal Crônica , Animais , Cinacalcete/farmacologia , Cinacalcete/uso terapêutico , Naftalenos/farmacologia , Hiperparatireoidismo Secundário/tratamento farmacológico , Hiperparatireoidismo Secundário/etiologia , Hormônio Paratireóideo/uso terapêutico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , CálcioRESUMO
PI3Kδ plays a critical role in adaptive immune cell activation and function. Suppression of PI3Kδ has been shown to counter excessive triggering of immune responses which has led to delineating the role of this isoform in the pathophysiology of autoimmune disorders. In the current study, we have described preclinical characterization of PI3Kδ specific inhibitor LL-00071210 in various rheumatoid arthritis models. LL-00071210 displayed excellent in vitro potency in biochemical and cellular assay against PI3Kδ with IC50 values of 24.6 nM and 9.4 nM, respectively. LL-00071210 showed higher selectivity over PI3Kγ and PI3Kß as compared to available PI3K inhibitors. LL-00071210 had good stability in liver microsomes and plasma across species and showed low clearance, low-to-moderate Vss, with bioavailability of >50% in preclinical species. LL-00071210 demonstrated excellent in vivo efficacy in adjuvant-induced and collagen-induced arthritis models. Co-administration of LL-00071210 and methotrexate at subtherapeutic dose regimen in collagen induced arthritis model led to additive effects, indicating the combination potential of LL-00071210 along with available disease modifying anti-rheumatic drugs (DMARD). In conclusion, we have described a specific PI3Kδ inhibitor with â¼100-fold selectivity over other PI3K isoforms. LL-00071210 has good drug-like properties and thus warrants testing in the clinic for the treatment of autoimmune diseases.
Assuntos
Artrite Reumatoide , Fosfatidilinositol 3-Quinases , Artrite Reumatoide/tratamento farmacológico , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Relação Estrutura-AtividadeRESUMO
α7 nicotinic acetylcholine receptor (α7 nAChR) is an extensively validated target for several neurological and psychiatric conditions namely, dementia and schizophrenia, owing to its vital roles in cognition and sensorimotor gating. Positive allosteric modulation (PAM) of α7 nAChR represents an innovative approach to amplify endogenous cholinergic signaling in a temporally restricted manner in learning and memory centers of brain. α7 nAChR PAMs are anticipated to side-step burgeoning issues observed with several clinical-stage orthosteric α7 nAChR agonists, related to selectivity, tolerance/tachyphylaxis, thus providing a novel dimension in therapeutic strategy and pharmacology of α7 nAChR ion-channel. Here we describe a novel α7 nAChR PAM, LL-00066471, which potently amplified agonist-induced Ca2+ fluxes in neuronal IMR-32 neuroblastoma cells in a α-bungarotoxin (α-BTX) sensitive manner. LL-00066471 showed excellent oral bioavailability across species (mouse, rat and dog), low clearance and good brain penetration (B/P ratio > 1). In vivo, LL-00066471 robustly attenuated cognitive deficits in both procognitive and antiamnesic paradigms of short-term episodic and recognition memory in novel object recognition task (NORT) and social recognition task (SRT), respectively. Additionally, LL-00066471 mitigated apomorphine-induced sensorimotor gating deficits in acoustic startle reflex (ASR) and enhanced antipsychotic efficacy of olanzapine in conditioned avoidance response (CAR) task. Further, LL-00066471 corrected redox-imbalances and reduced cortico-striatal infarcts in stroke model. These finding together suggest that LL-00066471 has potential to symptomatically alleviate cognitive deficits associated with dementias, attenuate sensorimotor gating deficits in schizophrenia and correct redox-imbalances in cerebrovascular disorders. Therefore, LL-00066471 presents potential for management of cognitive impairments associated with neurological and psychiatric conditions.
Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Colinérgicos/farmacologia , Cognição/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , Transtornos Neurológicos da Marcha/prevenção & controle , Filtro Sensorial/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Linhagem Celular Tumoral , Colinérgicos/farmacocinética , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Cães , Comportamento Exploratório/efeitos dos fármacos , Transtornos Neurológicos da Marcha/metabolismo , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Neurológicos da Marcha/psicologia , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/metabolismo , AVC Isquêmico/fisiopatologia , Masculino , Camundongos Endogâmicos BALB C , Teste de Campo Aberto/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Ratos Wistar , Reflexo de Sobressalto/efeitos dos fármacos , Transdução de Sinais , Comportamento Social , Receptor Nicotínico de Acetilcolina alfa7/metabolismoRESUMO
The role of calcium release-activated calcium (CRAC) channels is well characterized and is of particular importance in T-cell function. CRAC channels are involved in the pathogenesis of several autoimmune diseases, making it an attractive therapeutic target for treating inflammatory diseases, like rheumatoid arthritis (RA). A systematic structure-activity relationship study with the goal of optimizing lipophilicity successfully yielded two lead compounds, 36 and 37. Both compounds showed decent potency and selectivity and a remarkable pharmacokinetic profile. Further characterization in in vivo RA models and subsequent histopathological evaluation of tissues led to the identification of 36 as a clinical candidate. Compound 36 displayed an excellent safety profile and had a sufficient safety margin to qualify it for use in human testing. Oral administration of 36 in Phase 1 clinical study in healthy volunteers established favorable safety, tolerability, and good target engagement as measured by levels of IL-2 and TNF-α.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Ativados pela Liberação de Cálcio/antagonistas & inibidores , Cálcio/metabolismo , Descoberta de Drogas , Administração Oral , Animais , Área Sob a Curva , Artrite Reumatoide/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/farmacocinética , Ensaios Clínicos Fase I como Assunto , Humanos , Células Jurkat , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-AtividadeRESUMO
Voltage-gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all of the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic structure-activity relationship (SAR) studies carried out to identify novel sulfonamide derivatives as potent, selective, and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5, and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43, and 51 showed a favorable pharmacokinetics (PK) profile across different species and robust efficacy in veratridine and formalin-induced inflammatory pain models in mice. Compound 51 also showed significant effects on the CCI-induced neuropathic pain model. The profile of 51 indicated that it has the potential for further evaluation as a therapeutic for pain.
Assuntos
Cromanos/química , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Animais , Cromanos/farmacocinética , Cromanos/uso terapêutico , Citocromo P-450 CYP2C9/química , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Modelos Animais de Doenças , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Canal de Sódio Disparado por Voltagem NAV1.7/química , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/patologia , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêuticoRESUMO
PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20 to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34 has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.
Assuntos
Antineoplásicos/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Quinolizinas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/síntese química , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/farmacocinética , Cães , Descoberta de Drogas , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Quinolizinas/síntese química , Quinolizinas/metabolismo , Quinolizinas/farmacocinética , Células RAW 264.7 , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The discovery of a series of thiophenephenylsulfonamides as positive allosteric modulators (PAM) of α7 nicotinic acetylcholine receptor (α7 nAChR) is described. Optimization of this series led to identification of compound 28, a novel PAM of α7 nicotinic acetylcholine receptor (α7 nAChR). Compound 28 showed good in vitro potency, with pharmacokinetic profile across species with excellent brain penetration and residence time. Compound 28 robustly reversed the cognitive deficits in episodic/working memory in both time-delay and scopolamine-induced amnesia paradigms in the novel object and social recognition tasks, at very low dose levels. Additionally, compound 28 has shown excellent safety profile in phase 1 clinical trials and is being evaluated for efficacy and safety as monotherapy in patients with mild to moderate Alzheimer's disease.
Assuntos
Descoberta de Drogas , Agonistas Nicotínicos/farmacologia , Nootrópicos/farmacologia , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Doença de Alzheimer/tratamento farmacológico , Animais , Encéfalo/metabolismo , Ensaios Clínicos como Assunto , Estabilidade de Medicamentos , Humanos , Masculino , Estrutura Molecular , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/farmacocinética , Nootrópicos/síntese química , Nootrópicos/farmacocinética , Ratos Sprague-Dawley , Ratos Wistar , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Tiofenos/síntese química , Tiofenos/farmacocinéticaRESUMO
The identification of a novel class of potent pan-genotypic NS5A inhibitors with good pharmacokinetic profile suitable for potential use in treating HCV infections is disclosed here. The present series of compounds are with less complex tricyclic central core, identified through a systematic SAR study carried out on biphenyl moiety. The SAR outcome has confirmed the requirement of near planar and linear conformation of the molecule to achieve the best pan-genotypic activity. In addition, SAR with substituted imidazoles on improvement of antiviral activity is disclosed. The newly identified compounds 12, 16, 19-21 have shown desirable pharmacokinetic profiles with a favorable uptake of compounds in liver and maintained a significant concentration for up to 8 h in the liver. In addition, compounds 20 and 21 have shown superior pan-genotypic anti-HCV activity compared to ledipasvir and daclatasvir. Additional characterization and preliminary safety assessment resulted in the identification of compound 20 as a potential clinical candidate.