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1.
Bioorg Med Chem Lett ; 28(12): 2195-2200, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29764741

RESUMO

New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1-MDCK cell model was successfully applied. Compound 8a confirmed the in vitro results by dose-dependently reducing Aß levels in mice in an acute treatment regimen.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Oxazinas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células Madin Darby de Rim Canino/efeitos dos fármacos , Camundongos , Modelos Moleculares , Conformação Molecular , Oxazinas/síntese química , Oxazinas/química , Relação Estrutura-Atividade
2.
Cell Stem Cell ; 31(4): 554-569.e17, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38579685

RESUMO

The YAP/Hippo pathway is an organ growth and size regulation rheostat safeguarding multiple tissue stem cell compartments. LATS kinases phosphorylate and thereby inactivate YAP, thus representing a potential direct drug target for promoting tissue regeneration. Here, we report the identification and characterization of the selective small-molecule LATS kinase inhibitor NIBR-LTSi. NIBR-LTSi activates YAP signaling, shows good oral bioavailability, and expands organoids derived from several mouse and human tissues. In tissue stem cells, NIBR-LTSi promotes proliferation, maintains stemness, and blocks differentiation in vitro and in vivo. NIBR-LTSi accelerates liver regeneration following extended hepatectomy in mice. However, increased proliferation and cell dedifferentiation in multiple organs prevent prolonged systemic LATS inhibition, thus limiting potential therapeutic benefit. Together, we report a selective LATS kinase inhibitor agonizing YAP signaling and promoting tissue regeneration in vitro and in vivo, enabling future research on the regenerative potential of the YAP/Hippo pathway.


Assuntos
Inibidores de Proteínas Quinases , Proteínas Serina-Treonina Quinases , Proteínas de Sinalização YAP , Animais , Humanos , Camundongos , Proliferação de Células , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Células-Tronco/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAP/agonistas , Proteínas de Sinalização YAP/efeitos dos fármacos , Proteínas de Sinalização YAP/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia
3.
Bioorg Med Chem Lett ; 23(19): 5300-6, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23981898

RESUMO

Previous structure based optimization in our laboratories led to the identification of a novel, high-affinity cyclic sulfone hydroxyethylamine-derived inhibitor such as 1 that lowers CNS-derived Aß following oral administration to transgenic APP51/16 mice. Herein we report SAR development in the S3 and S2' subsites of BACE1 for cyclic sulfoxide hydroxyethyl amine inhibitors, the synthetic approaches employed in this effort, and in vivo data for optimized compound such as 11d.


Assuntos
Secretases da Proteína Precursora do Amiloide/efeitos dos fármacos , Peptídeos beta-Amiloides/química , Ácido Aspártico Endopeptidases/efeitos dos fármacos , Descoberta de Drogas , Etanolaminas/farmacologia , Sulfóxidos/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/sangue , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Química Encefálica , Cristalografia por Raios X , Ciclização , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Etanolaminas/química , Feminino , Concentração Inibidora 50 , Masculino , Camundongos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Especificidade por Substrato , Sulfóxidos/química
4.
J Med Chem ; 65(24): 16173-16203, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36399068

RESUMO

Rapid emergence of tumor resistance via RAS pathway reactivation has been reported from clinical studies of covalent KRASG12C inhibitors. Thus, inhibitors with broad potential for combination treatment and distinct binding modes to overcome resistance mutations may prove beneficial. JDQ443 is an investigational covalent KRASG12C inhibitor derived from structure-based drug design followed by extensive optimization of two dissimilar prototypes. JDQ443 is a stable atropisomer containing a unique 5-methylpyrazole core and a spiro-azetidine linker designed to position the electrophilic acrylamide for optimal engagement with KRASG12C C12. A substituted indazole at pyrazole position 3 results in novel interactions with the binding pocket that do not involve residue H95. JDQ443 showed PK/PD activity in vivo and dose-dependent antitumor activity in mouse xenograft models. JDQ443 is now in clinical development, with encouraging early phase data reported from an ongoing Phase Ib/II clinical trial (NCT04699188).


Assuntos
Neoplasias , Proteínas Proto-Oncogênicas p21(ras) , Animais , Humanos , Camundongos , Modelos Animais de Doenças , Desenho de Fármacos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Pirazóis/farmacologia , Pirazóis/uso terapêutico
5.
J Med Chem ; 64(20): 15262-15279, 2021 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-34648711

RESUMO

After identification of lead compound 6, 5-amino-1,4-oxazine BACE1 inhibitors were optimized in order to improve potency, brain penetration, and metabolic stability. Insertion of a methyl and a trifluoromethyl group at the 6-position of the 5-amino-1,4-oxazine led to 8 (NB-360), an inhibitor with a pKa of 7.1, a very low P-glycoprotein efflux ratio, and excellent pharmacological profile, enabling high central nervous system penetration and exposure. Fur color changes observed with NB-360 in efficacy studies in preclinical animal models triggered further optimization of the series. Herein, we describe the steps leading to the discovery of 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide 15 (CNP520, umibecestat), an inhibitor with superior BACE1/BACE2 selectivity and pharmacokinetics. CNP520 reduced significantly Aß levels in mice and rats in acute and chronic treatment regimens without any side effects and thus qualified for Alzheimer's disease prevention studies in the clinic.


Assuntos
Doença de Alzheimer/prevenção & controle , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Oxazinas/farmacologia , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Linhagem Celular , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oxazinas/síntese química , Oxazinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
6.
J Med Chem ; 64(8): 4677-4696, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33844524

RESUMO

Starting from lead compound 4, the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF3 group delivered an excellent pharmacological profile with a pKa of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure. Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent N-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 (NB-360), able to reduce significantly Aß levels in mice, rats, and dogs in acute and chronic treatment regimens.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Inibidores Enzimáticos/síntese química , Ácidos Picolínicos/síntese química , Tiazinas/síntese química , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Encéfalo/metabolismo , Cristalografia por Raios X , Cães , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Meia-Vida , Humanos , Camundongos , Simulação de Dinâmica Molecular , Oxazinas/química , Ácidos Picolínicos/farmacocinética , Ácidos Picolínicos/uso terapêutico , Ratos , Relação Estrutura-Atividade , Tiazinas/farmacocinética , Tiazinas/uso terapêutico
7.
Bioorg Med Chem Lett ; 20(2): 603-7, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19963375

RESUMO

A series of macrocyclic peptidic BACE-1 inhibitors was designed. While potency on BACE-1 was rather high, the first set of compounds showed poor brain permeation and high efflux in the MDRI-MDCK assay. The replacement of the secondary benzylamino group with a phenylcyclopropylamino group maintained potency on BACE-1, while P-glycoprotein-mediated efflux was significantly reduced and brain permeation improved. Several compounds from this series demonstrated acute reduction of Abeta in human APP-wildtype transgenic (APP51/16) mice after oral administration.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Benzamidas/química , Encéfalo/metabolismo , Lactamas/química , Compostos Macrocíclicos/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Benzamidas/síntese química , Benzamidas/farmacologia , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Humanos , Lactamas/síntese química , Lactamas/farmacologia , Compostos Macrocíclicos/farmacologia , Camundongos , Camundongos Transgênicos , Estereoisomerismo , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 19(5): 1361-5, 2009 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-19195886
9.
Bioorg Med Chem Lett ; 19(5): 1366-70, 2009 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-19195887

RESUMO

The macrocyclic peptidic BACE-1 inhibitors 2a-c show moderate enzymatic and cellular activity. By exchange of the hydroxyethylene- to ethanolamine-transition state mimetic the peptidic character was reduced, providing the highly potent and selective inhibitor 3. Variation of the P' moiety resulted in the macrocyclic inhibitor 14. Both macrocycles show inhibition of BACE-1 in the brain of APP51/16 transgenic mice, 3 (NB-544) after intravenous and 14 (NB-533) after oral application.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Fragmentos de Peptídeos/química , Inibidores de Proteases/química , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/química , Ácido Aspártico Endopeptidases/metabolismo , Células CHO , Cricetinae , Cricetulus , Cristalografia por Raios X , Humanos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fragmentos de Peptídeos/farmacologia , Inibidores de Proteases/farmacologia , Estrutura Secundária de Proteína/fisiologia
10.
Br J Pharmacol ; 176(18): 3435-3446, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30657591

RESUMO

Inhibition of ß-secretase 1 (BACE-1; also known as ß-site amyloid precursor protein-cleaving enzyme-1) is a current approach to fight the amyloid-ß (Aß) deposition in the brains of patients with Alzheimer's disease, and a number of BACE-1 inhibitors are being tested in clinical trials. The BACE-1 inhibitor NB-360, although not a clinical compound, turned out to be a valuable pharmacological tool to investigate the effects of BACE-1 inhibition on the deposition of different Aß species in amyloid precursor protein (APP) transgenic mice. Furthermore, chronic animal studies with NB-360 revealed relationships between BACE-1 inhibition, Aß deposition, and Aß-related downstream effects on neuroinflammation, neuronal function, and markers of neurodegeneration. NB-360 effects on the processing of physiological BACE-1 substrates as well as on nonenzymatic BACE-1 functions have been investigated, complementing studies in BACE-1 knockout mice. Because NB-360 is also an inhibitor for BACE-2, nonclinical studies in adult animals revealed physiological effects of BACE-2 inhibition. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácidos Picolínicos/uso terapêutico , Tiazinas/uso terapêutico , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Humanos
11.
ACS Chem Biol ; 14(4): 587-593, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30763067

RESUMO

The oncogenic V617F mutation lies in the pseudokinase domain of JAK2, marking it as a potential target for development of compounds that might inhibit the pathogenic activity of the mutant protein. We used differential scanning fluorimetry to identify compounds that bind the JAK2 pseudokinase domain. Crystal structures of five candidate compounds with the wild-type domain reveal their modes of binding. Exploration of analogs of screening hit BI-D1870 led to the identification of compound 2, a 123 nM ligand for the pseudokinase domain. Interestingly, crystal structures of the V617F domain in complex with two unrelated compounds reveal a conformation that is characteristic of the wild-type domain, rather than that previously observed for the V617F mutant. These structures suggest that certain ATP-site ligands can modulate the V617F allosteric site, thereby providing a mechanistic rationale for targeting the pseudokinase domain and a structural foundation for development of more potent and pseudokinase-selective compounds.


Assuntos
Trifosfato de Adenosina/metabolismo , Janus Quinase 2/metabolismo , Mutação , Linhagem Celular , Cristalografia por Raios X , Humanos , Janus Quinase 2/química , Janus Quinase 2/genética , Ligantes , Fosforilação , Conformação Proteica
12.
EMBO Mol Med ; 10(11)2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30224383

RESUMO

The beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) initiates the generation of amyloid-ß (Aß), and the amyloid cascade leading to amyloid plaque deposition, neurodegeneration, and dementia in Alzheimer's disease (AD). Clinical failures of anti-Aß therapies in dementia stages suggest that treatment has to start in the early, asymptomatic disease states. The BACE-1 inhibitor CNP520 has a selectivity, pharmacodynamics, and distribution profile suitable for AD prevention studies. CNP520 reduced brain and cerebrospinal fluid (CSF) Aß in rats and dogs, and Aß plaque deposition in APP-transgenic mice. Animal toxicology studies of CNP520 demonstrated sufficient safety margins, with no signs of hair depigmentation, retina degeneration, liver toxicity, or cardiovascular effects. In healthy adults ≥ 60 years old, treatment with CNP520 was safe and well tolerated and resulted in robust and dose-dependent Aß reduction in the cerebrospinal fluid. Thus, long-term, pivotal studies with CNP520 have been initiated in the Generation Program.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/prevenção & controle , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Oxazinas/uso terapêutico , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/líquido cefalorraquidiano , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Astrócitos/metabolismo , Encéfalo/patologia , Catepsina D/antagonistas & inibidores , Catepsina D/metabolismo , Hemorragia Cerebral/patologia , Feminino , Hominidae/genética , Humanos , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/metabolismo , Oxazinas/sangue , Oxazinas/química , Oxazinas/farmacologia , Pesquisa Translacional Biomédica
13.
ACS Med Chem Lett ; 8(3): 338-343, 2017 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-28337327

RESUMO

Misdirected catalytic activity of histone methyltransferase Dot1L is believed to be causative for a subset of highly aggressive acute leukemias. Targeting the catalytic domain of Dot1L represents a potential therapeutic approach for these leukemias. In the context of a comprehensive Dot1L hit finding strategy, a knowledge-based virtual screen of the Dot1L SAM binding pocket led to the discovery of 2, a non-nucleoside fragment mimicking key interactions of SAM bound to Dot1L. Fragment linking of 2 and 3, an induced back pocket binder identified in earlier studies, followed by careful ligand optimization led to the identification of 7, a highly potent, selective and structurally novel Dot1L inhibitor.

14.
ACS Med Chem Lett ; 7(8): 735-40, 2016 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-27563395

RESUMO

Oncogenic MLL fusion proteins aberrantly recruit Dot1L, a histone methyltransferase, to ectopic loci, leading to local hypermethylation of H3K79 and misexpression of HoxA genes driving MLL-rearranged leukemias. Inhibition of the methyltransferase activity of Dot1L in this setting is predicted to reverse aberrant H3K79 methylation, leading to repression of leukemogenic genes and tumor growth inhibition. In the context of our Dot1L drug discovery program, high-throughput screening led to the identification of 2, a weak Dot1L inhibitor with an unprecedented, induced pocket binding mode. A medicinal chemistry campaign, strongly guided by structure-based consideration and ligand-based morphing, enabled the discovery of 12 and 13, potent, selective, and structurally completely novel Dot1L inhibitors.

15.
Sci Rep ; 6: 21917, 2016 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-26912421

RESUMO

Melanocytes of the hair follicle produce melanin and are essential in determining the differences in hair color. Pigment cell-specific MELanocyte Protein (PMEL17) plays a crucial role in melanogenesis. One of the critical steps is the amyloid-like functional oligomerization of PMEL17. Beta Site APP Cleaving Enzyme-2 (BACE2) and γ-secretase have been shown to be key players in generating the proteolytic fragments of PMEL17. The ß-secretase (BACE1) is responsible for the generation of amyloid-ß (Aß) fragments in the brain and is therefore proposed as a therapeutic target for Alzheimer's disease (AD). Currently BACE1 inhibitors, most of which lack selectivity over BACE2, have demonstrated efficacious reduction of amyloid-ß peptides in animals and the CSF of humans. BACE2 knock-out mice have a deficiency in PMEL17 proteolytic processing leading to impaired melanin storage and hair depigmentation. Here, we confirm BACE2-mediated inhibition of PMEL17 proteolytic processing in vitro in mouse and human melanocytes. Furthermore, we show that wildtype as well as bace2(+/-) and bace2(-/-) mice treated with a potent dual BACE1/BACE2 inhibitor NB-360 display dose-dependent appearance of irreversibly depigmented hair. Retinal pigmented epithelium showed no morphological changes. Our data demonstrates that BACE2 as well as additional BACE1 inhibition affects melanosome maturation and induces hair depigmentation in mice.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Cabelo/metabolismo , Antígeno gp100 de Melanoma/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/genética , Western Blotting , Linhagem Celular Tumoral , Feminino , Cabelo/efeitos dos fármacos , Cabelo/patologia , Humanos , Masculino , Melaninas/metabolismo , Melanócitos/citologia , Melanócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Fluorescência , Fragmentos de Peptídeos/metabolismo , Ácidos Picolínicos/farmacologia , Pigmentação/efeitos dos fármacos , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Inibidores de Proteases/farmacologia , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Tiazinas/farmacologia , Úvea/efeitos dos fármacos , Úvea/metabolismo , Úvea/patologia , Antígeno gp100 de Melanoma/antagonistas & inibidores
16.
Mol Neurodegener ; 10: 44, 2015 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-26336937

RESUMO

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia, the number of affected individuals is rising, with significant impacts for healthcare systems. Current symptomatic treatments delay, but do not halt, disease progression. Genetic evidence points to aggregation and deposition of amyloid-ß (Aß) in the brain being causal for the neurodegeneration and dementia typical of AD. Approaches to target Aß via inhibition of γ-secretase or passive antibody therapy have not yet resulted in substantial clinical benefits. Inhibition of BACE1 (ß-secretase) has proven a challenging concept, but recent BACE1inhibitors can enter the brain sufficiently well to lower Aß. However, failures with the first clinical BACE1 inhibitors have highlighted the need to generate compounds with appropriate efficacy and safety profiles, since long treatment periods are expected to be necessary in humans. RESULTS: Treatment with NB-360, a potent and brain penetrable BACE-1 inhibitor can completely block the progression of Aß deposition in the brains of APP transgenic mice, a model for amyloid pathology. We furthermore show that almost complete reduction of Aß was achieved also in rats and in dogs, suggesting that these findings are translational across species and can be extrapolated to humans. Amyloid pathology may be an initial step in a complex pathological cascade; therefore we investigated the effect of BACE-1 inhibition on neuroinflammation, a prominent downstream feature of the disease. NB-360 stopped accumulation of activated inflammatory cells in the brains of APP transgenic mice. Upon chronic treatment of APP transgenic mice, patches of grey hairs appeared. CONCLUSIONS: In a rapidly developing field, the data on NB-360 broaden the chemical space and expand knowledge on the properties that are needed to make a BACE-1 inhibitor potent and safe enough for long-term use in patients. Due to its excellent brain penetration, reasonable oral doses of NB-360 were sufficient to completely block amyloid-ß deposition in an APP transgenic mouse model. Data across species suggest similar treatment effects can possibly be achieved in humans. The reduced neuroinflammation upon amyloid reduction by NB-360 treatment supports the notion that targeting amyloid-ß pathology can have beneficial downstream effects on the progression of Alzheimer's disease.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Fármacos Neuroprotetores/uso terapêutico , Ácidos Picolínicos/uso terapêutico , Tiazinas/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/fisiologia , Peptídeos beta-Amiloides/genética , Animais , Ácido Aspártico Endopeptidases/fisiologia , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Células CHO , Cricetinae , Cricetulus , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Cor de Cabelo/efeitos dos fármacos , Humanos , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/patologia , Mutação , Proteínas do Tecido Nervoso/fisiologia , Fármacos Neuroprotetores/farmacocinética , Fragmentos de Peptídeos/metabolismo , Ácidos Picolínicos/química , Ácidos Picolínicos/farmacocinética , Ratos , Proteínas Recombinantes de Fusão/metabolismo , Tiazinas/química , Tiazinas/farmacocinética
17.
J Med Chem ; 55(7): 3364-86, 2012 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-22380629

RESUMO

Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure-activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC(50) values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 µmol/kg demonstrated significant reduction of brain Aß levels.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Encéfalo/metabolismo , Óxidos S-Cíclicos/síntese química , Etilaminas/síntese química , Sulfonas/síntese química , Animais , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Cricetinae , Cricetulus , Cristalografia por Raios X , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacologia , Cães , Desenho de Fármacos , Etilaminas/química , Etilaminas/farmacologia , Humanos , Indazóis/síntese química , Indazóis/química , Indazóis/farmacologia , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologia
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