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1.
Bioorg Med Chem ; 28(1): 115194, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31786008

RESUMO

Inhibition of BACE1 has become an important strategy in the quest for disease modifying agents to slow the progression of Alzheimer's disease. We previously reported the fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aß in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 inhibitor that reached phase 2 clinical trials. Herein we describe the preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans-cyclopropyl moieties as conformational constraints. The design, details of the stereochemically complex organic synthesis, and biological activity of these BACE1 inhibitors is described.

2.
Eur J Med Chem ; 182: 111643, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31514017

RESUMO

Developing drugs for CNS related diseases continues to be one of the most challenging endeavors in drug discovery. This is at least in part related to the existence of the Blood Brain Barrier (BBB), a complex multicellular organization that provides selective access to required nutrients and hormones, while removing waste and restricting exposure to potential harmful toxins, pathogens, and xenobiotics. Consequently, designing and selecting molecules that can overcame this protection system are unique and critical aspects of the CNS drug discovery. Here we review modern CNS pharmacokinetic concepts and methods suitable for early drug discovery, and medicinal chemistry strategies towards molecules with optimal CNS exposure.


Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Descoberta de Drogas , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/química , Sistemas de Liberação de Medicamentos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 164: 391-398, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30611980

RESUMO

Although pediatric leukemia is generally treatable, certain leukemic subtypes face poor prognosis in the clinic suggesting new selective therapeutic agents are needed. Thus, to identify selective apoptosis inducers, a small-molecule library screening approach was conducted using an isogenic leukemic murine p185+ B-ALL cell line pair (BCR-ABL-WT and the BAX/BAK deficient BCR-ABL-DKO). Gratifyingly, the investigation revealed several compounds featuring substituted aromatic five-membered-ring heterocycles with significant activity against murine and human leukemic cellular models. The identified compounds represent potentially novel antileukemic molecular scaffolds exemplified by compounds 1, 2 and 7, which demonstrated EC50 values in the nanomolar and low micromolar range against various leukemia subtypes (SUP-B15, KOPN-8, NALM-06, UoC-B1 cellular models) and pro-apoptotic properties in solid tumor cell models (MDA-MB-231, SUM149) with ample therapeutic index in normal cells. Herein, we highlight compounds 1, 2 and 7 which promote cell death mediated by caspase 3/7 induction. Our study establishes a strategic platform for the development of potent and selective anti-leukemic agents.


Assuntos
Antineoplásicos/farmacologia , Compostos Heterocíclicos/uso terapêutico , Leucemia/tratamento farmacológico , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspases/genética , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos/métodos , Indução Enzimática/efeitos dos fármacos , Compostos Heterocíclicos/química , Humanos , Camundongos , Bibliotecas de Moléculas Pequenas/uso terapêutico , Índice Terapêutico
5.
J Med Chem ; 61(17): 7700-7709, 2018 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-30091915

RESUMO

There are currently no FDA-approved therapies to prevent the hearing loss associated with the usage of cisplatin in chemotherapeutic regimens. We recently demonstrated that the pharmacologic inhibition with kenpaullone or genetic deletion of CDK2 preserved hearing function in animal models treated with cisplatin, which suggests that CDK2 is a promising therapeutic target to prevent cisplatin-induced ototoxicity. In this study, we identified two lead compounds, AT7519 and AZD5438, from a focused library screen of 187 CDK2 inhibitors, performed in an immortalized cell line derived from neonatal mouse cochleae treated with cisplatin. Moreover, we screened 36 analogues of AT7519 and identified analogue 7, which exhibited an improved therapeutic index. When delivered locally, analogue 7 and AZD5438 both provided significant protection against cisplatin-induced ototoxicity in mice. Thus, we have identified two additional compounds that prevent cisplatin-induced ototoxicity in vivo and provided further evidence that CDK2 is a druggable target for treating cisplatin-induced ototoxicity.


Assuntos
Cisplatino/efeitos adversos , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Perda Auditiva/induzido quimicamente , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/efeitos adversos , Cóclea/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Perda Auditiva/prevenção & controle , Humanos , Imidazóis/química , Imidazóis/farmacologia , Camundongos Endogâmicos , Técnicas de Cultura de Órgãos , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade
6.
J Med Chem ; 60(14): 5943-5954, 2017 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-28388050

RESUMO

Understanding the "limits and boundaries" of the central nervous system (CNS) property space is a critical aspect of modern CNS drug design. Medicinal chemists are often guided by the physicochemical properties of marketed CNS drugs, which are heavily biased toward "traditional" aminergic targets and commonly described as small lipophilic amines. This miniperspective describes the statistical analysis of the calculated physicochemical properties for a diverse set of ligands for mostly "nontraditional" CNS targets and classified as either "brain penetrant" or "peripherally restricted" on the basis of the experimental mouse brain exposure. The results suggested that (a) the physicochemical property space conducive to brain exposure is larger than the one defined by the marketed CNS drugs and (b) the most critical brain exposure determinants are descriptors of the molecular size and hydrogen bond capacity. These findings led to a modified version of the CNS MPO scoring algorithm, termed CNS MPO.v2.


Assuntos
Encéfalo/metabolismo , Fármacos do Sistema Nervoso Central/química , Fármacos do Sistema Nervoso Central/farmacocinética , Administração Oral , Animais , Barreira Hematoencefálica/metabolismo , Físico-Química , Bases de Dados de Compostos Químicos , Camundongos , Permeabilidade
7.
Bioorg Med Chem Lett ; 26(2): 241-250, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26707396

RESUMO

G protein coupled receptors have historically been one of the most druggable classes of cellular proteins. The members of this large receptor gene family couple to primary effectors, G proteins, that have built in mechanisms for regeneration and amplification of signaling with each engagement of receptor and ligand, a kinetic event in itself. In recent years GPCRs, have been found to interact with arrestin proteins to initiate signal propagation in the absence of G protein interactions. This pinnacle observation has changed a previously held notion of the linear spectrum of GPCR efficacy and uncovered a new paradigm in GPCR research and drug discovery that relies on multidimensionality of GPCR signaling. Ligands were found that selectively confer activity in one pathway over another, and this phenomenon has been referred to as 'biased agonism' or 'functional selectivity'. While great strides in the understanding of this phenomenon have been made in recent years, two critical questions still dominate the field: How can we rationally design biased GPCR ligands, and ultimately, which physiological responses are due to G protein versus arrestin interactions? This review will discuss the current understanding of some of the key aspects of biased signaling that are related to these questions, including mechanistic insights in the nature of biased signaling and methods for measuring ligand bias, as well as relevant examples of drug discovery applications and medicinal chemistry strategies that highlight the challenges and opportunities in this rapidly evolving field.


Assuntos
Arrestinas/agonistas , Descoberta de Drogas , Receptores Acoplados a Proteínas-G/agonistas , Animais , Arrestinas/fisiologia , Humanos , Ligantes , Modelos Moleculares , Receptores Acoplados a Proteínas-G/fisiologia
8.
J Med Chem ; 58(6): 2584-608, 2015 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-25494650

RESUMO

The human brain is a uniquely complex organ, which has evolved a sophisticated protection system to prevent injury from external insults and toxins. Designing molecules that can overcome this protection system and achieve optimal concentration at the desired therapeutic target in the brain is a specific and major challenge for medicinal chemists working in CNS drug discovery. Analogous to the now widely accepted rule of 5 in the design of oral drugs, the physicochemical properties required for optimal brain exposure have been extensively studied in an attempt to similarly define the attributes of successful CNS drugs and drug candidates. This body of work is systematically reviewed here, with a particular emphasis on the interplay between the most critical physicochemical and pharmacokinetic parameters of CNS drugs as well as their impact on medicinal chemistry strategies toward molecules with optimal brain exposure. A summary of modern CNS pharmacokinetic concepts and methods is also provided.


Assuntos
Encéfalo/metabolismo , Fármacos do Sistema Nervoso Central/química , Fármacos do Sistema Nervoso Central/farmacocinética , Desenho de Fármacos , Animais , Transporte Biológico Ativo , Barreira Hematoencefálica/metabolismo , Humanos , Modelos Moleculares , Permeabilidade
9.
Bioorg Med Chem Lett ; 21(1): 137-40, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21129964

RESUMO

High-throughput screening of 3.87 million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed progression from a non-selective ligand with a poor ADMET profile to an orally bioavailable, selective, stable, glucocorticoid receptor antagonist.


Assuntos
Receptores de Glucocorticoides/antagonistas & inibidores , Animais , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Hidrocortisona/química , Microssomos/metabolismo , Ratos , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética
10.
Bioorg Med Chem Lett ; 21(1): 97-101, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21145740

RESUMO

Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivatives which were profiled in the primary ROCK-I IMAP assay. Compounds 23A and 23E were selected as fragment optimized hits for further profiling. Compound 23A has similar ROCK-1 affinity, potency and cell based efficacy to the first generation ROCK inhibitors, however, it has a superior PK profile in C57 mouse. Compound 23E demonstrates the feasibility of improving ROCK-1 affinity, potency and cell based efficacy for the series, however, it has a poor PK profile relative to 23A.


Assuntos
Aminas/química , Isoquinolinas/química , Inibidores de Proteínas Quinases/química , Quinases Associadas a rho/antagonistas & inibidores , Aminas/síntese química , Aminas/farmacocinética , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Isoquinolinas/síntese química , Isoquinolinas/farmacocinética , Camundongos , Camundongos Endogâmicos C57BL , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-Atividade , Quinases Associadas a rho/metabolismo
12.
Bioorg Med Chem Lett ; 20(23): 6890-4, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-21030256

RESUMO

The trifluoromethylphenyl P2 motif from previously reported heteroarylnitrile series has been successfully applied for the design and synthesis of highly potent novel ketoamide-based cathepsin S inhibitors. The key in this process is the change of the torsion angle between the P2 phenyl ring and the attached secondary amide by adding a small Cl, F, or Me group at the 2-position.


Assuntos
Compostos de Anilina/síntese química , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Amidas/síntese química , Amidas/farmacologia , Compostos de Anilina/farmacologia , Animais , Inibidores de Cisteína Proteinase/farmacologia , Flúor , Humanos , Cetonas , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 20(21): 6237-41, 2010 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-20843687

RESUMO

Several structure-guided optimisation strategies were explored in order to improve the hERG selectivity profile of cathepsin K inhibitor 1, whilst maintaining its otherwise excellent in vitro and in vivo profile. Ultimately, attenuation of clogP and pK(a) properties proved a successful approach and led to the discovery of a potent analogue 23, which, in addition to the desired selectivity over hERG (>1000-fold), displayed a highly attractive overall profile.


Assuntos
Catepsina K/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Nitrilos/síntese química , Nitrilos/farmacologia , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Desenho de Fármacos , Descoberta de Drogas , Indicadores e Reagentes , Modelos Moleculares , Curva ROC , Relação Estrutura-Atividade , Torsades de Pointes/tratamento farmacológico
17.
Bioorg Med Chem Lett ; 20(15): 4350-4, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20598883

RESUMO

6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile analogues were identified as potent and selective cathepsin S inhibitor against both purified enzyme and in human JY cell based cellular assays. This core has a very stable thio-trapping nitrile war-head in comparison with the well reported pyrimidine-2-carbonitrile cysteine cathepsin inhibitors. Compound 47 is also very potent in in vivo mouse spleenic Lip10 accumulation assays.


Assuntos
Catepsinas/antagonistas & inibidores , Nitrilos/química , Inibidores de Proteases/química , Piridinas/química , Animais , Sítios de Ligação , Catepsinas/metabolismo , Linhagem Celular , Cristalografia por Raios X , Humanos , Camundongos , Nitrilos/síntese química , Nitrilos/farmacocinética , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Relação Estrutura-Atividade
19.
Bioorg Med Chem Lett ; 20(12): 3713-6, 2010 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-20471831

RESUMO

Antagonists of the 5-HT(6) receptor have been shown to improve cognitive function in a wide range of animal models and as such may prove to be attractive agents for the symptomatic treatment of cognitive disorders such as Alzheimer's disease (AD) and schizophrenia. We report herein the identification and SAR around N-(2-aminoalkyl)-1-(arylsulfonyl)indoline-3-carboxamides-a novel chemotype of 5-HT(6) antagonists.


Assuntos
Amidas/química , Indóis/química , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/síntese química , Amidas/farmacologia , Animais , Disponibilidade Biológica , Descoberta de Drogas , Humanos , Indóis/farmacologia , Masculino , Microssomos , Farmacocinética , Ratos , Ratos Wistar , Agonistas do Receptor de Serotonina/química , Relação Estrutura-Atividade
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