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1.
Drug Metab Dispos ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578209

RESUMO

We present a model for volume of distribution at steady-state (VDss) prediction, via fraction unbound in tissues (fut), from the Øie-Tozer equation as an extension of our and other authors previous work. It based on easily determined or computed physicochemical descriptors such as logD7.4 and fi (7.4) (cationic fraction ionized at pH 7.4) in addition to fraction unbound in plasma (fup). We had collected, as part of other work, an extensive dataset of VDss and fup values and used the descriptors above, gathered from the literature, for a preliminary assessment of the robustness of the method applied to 191 different compounds belonging to different charge classes and scaffolds. After this step we addressed the use of easily computed physicochemical descriptors and experimentally derived fup on the same data set and compare the results between the two approaches and against the Øie-Tozer equation using in vivo data. This approach positions itself between fully computational models and scaling methods based on in vivo animal models or in vitro Kp (tissue:plasma) data utilizing model tissues. We consider it a useful and orthogonal complement to the two very diverse approaches mentioned yet requiring minimal in vitro experimental work. It offers a relatively inexpensive, rapid, intuitive and simple way to predict VDss in human, at a relatively early stage of the drug discovery. SIGNIFICANCE STATEMENT: This method allows the prediction of VDss for small molecules in human without the use of animal PK data since it utilizes only in vitro data. It is therefore amenable to use at early stages, simple, intuitive, animal-sparing and quite accurate and it may serve scaling efforts well. Furthermore, utilizing the same dataset, we show that the performance of a model using computed pKa and logD7.4, still using experimental fup, compares well with the model using experimentally derived values.

2.
J Med Chem ; 61(18): 8120-8135, 2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30137981

RESUMO

Chronic myelogenous leukemia (CML) arises from the constitutive activity of the BCR-ABL1 oncoprotein. Tyrosine kinase inhibitors (TKIs) that target the ATP-binding site have transformed CML into a chronic manageable disease. However, some patients develop drug resistance due to ATP-site mutations impeding drug binding. We describe the discovery of asciminib (ABL001), the first allosteric BCR-ABL1 inhibitor to reach the clinic. Asciminib binds to the myristate pocket of BCR-ABL1 and maintains activity against TKI-resistant ATP-site mutations. Although resistance can emerge due to myristate-site mutations, these are sensitive to ATP-competitive inhibitors so that combinations of asciminib with ATP-competitive TKIs suppress the emergence of resistance. Fragment-based screening using NMR and X-ray yielded ligands for the myristate pocket. An NMR-based conformational assay guided the transformation of these inactive ligands into ABL1 inhibitors. Further structure-based optimization for potency, physicochemical, pharmacokinetic, and drug-like properties, culminated in asciminib, which is currently undergoing clinical studies in CML patients.

3.
Drug Metab Dispos ; 46(11): 1466-1477, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30115648

RESUMO

We report a trend analysis of human intravenous pharmacokinetic data on a data set of 1352 drugs. The aim in building this data set and its detailed analysis was to provide, as in the previous case published in 2008, an extended, robust, and accurate resource that could be applied by drug metabolism, clinical pharmacology, and medicinal chemistry scientists to a variety of scaling approaches. All in vivo data were obtained or derived from original references, either through the literature or regulatory agency reports, exclusively from studies utilizing intravenous administration. Plasma protein binding data were collected from other available sources to supplement these pharmacokinetic data. These parameters were analyzed concurrently with a range of physicochemical properties, and resultant trends and patterns within the data are presented. In addition, the date of first disclosure of each molecule was reported and the potential "temporal" impact on data trends was analyzed. The findings reported here are consistent with earlier described trends between pharmacokinetic behavior and physicochemical properties. Furthermore, the availability of a large data set of pharmacokinetic data in humans will be important to further pursue analyses of physicochemical properties, trends, and modeling efforts and should propel our deeper understanding (especially in terms of clearance) of the absorption, distribution, metabolism, and excretion behavior of drug compounds.

4.
J Med Chem ; 61(7): 2837-2864, 2018 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-29562737

RESUMO

In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs). The steroid-based anti-estrogen fulvestrant (5), the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies. Its efficacy, however, may be limited due to its poor physicochemical properties. We describe the design and synthesis of a series of potent benzothiophene-containing compounds that exhibit oral bioavailability and preclinical activity as SERDs. This article culminates in the identification of LSZ102 (10), a compound in clinical development for the treatment of ERα positive breast cancer.

5.
J Med Chem ; 60(22): 9097-9113, 2017 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-28609624

RESUMO

In silico tools to investigate absorption, distribution, metabolism, excretion, and pharmacokinetics (ADME-PK) properties of new chemical entities are an integral part of the current industrial drug discovery paradigm. While many companies are active in the field, scientists engaged in this area do not necessarily share the same background and have limited resources when seeking guidance on how to initiate and maintain an in silico ADME-PK infrastructure in an industrial setting. This work summarizes the views of a group of industrial in silico and experimental ADME scientists, participating in the In Silico ADME Working Group, a subgroup of the International Consortium for Innovation through Quality in Pharmaceutical Development (IQ) Drug Metabolism Leadership Group. This overview on the benefits, caveats, and impact of in silico ADME-PK should serve as a resource for medicinal chemists, computational chemists, and DMPK scientists working in drug design to increase their knowledge in the area.


Assuntos
Simulação por Computador , Descoberta de Drogas , Farmacocinética , Tecnologia Farmacêutica/métodos , Modelos Químicos , Relação Quantitativa Estrutura-Atividade
6.
J Med Chem ; 60(7): 2790-2818, 2017 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-28296398

RESUMO

Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.


Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Mama/efeitos dos fármacos , Receptor alfa de Estrogênio/antagonistas & inibidores , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/uso terapêutico , Acrilatos/química , Acrilatos/farmacocinética , Acrilatos/farmacologia , Acrilatos/uso terapêutico , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Cães , Descoberta de Drogas , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Células MCF-7 , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Proteólise/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacocinética , Tetra-Hidroisoquinolinas/farmacologia
7.
Nature ; 543(7647): 733-737, 2017 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-28329763

RESUMO

Chronic myeloid leukaemia (CML) is driven by the activity of the BCR-ABL1 fusion oncoprotein. ABL1 kinase inhibitors have improved the clinical outcomes for patients with CML, with over 80% of patients treated with imatinib surviving for more than 10 years. Second-generation ABL1 kinase inhibitors induce more potent molecular responses in both previously untreated and imatinib-resistant patients with CML. Studies in patients with chronic-phase CML have shown that around 50% of patients who achieve and maintain undetectable BCR-ABL1 transcript levels for at least 2 years remain disease-free after the withdrawal of treatment. Here we characterize ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia. In contrast to catalytic-site ABL1 kinase inhibitors, ABL001 binds to the myristoyl pocket of ABL1 and induces the formation of an inactive kinase conformation. ABL001 and second-generation catalytic inhibitors have similar cellular potencies but distinct patterns of resistance mutations, with genetic barcoding studies revealing pre-existing clonal populations with no shared resistance between ABL001 and the catalytic inhibitor nilotinib. Consistent with this profile, acquired resistance was observed with single-agent therapy in mice; however, the combination of ABL001 and nilotinib led to complete disease control and eradicated CML xenograft tumours without recurrence after the cessation of treatment.


Assuntos
Sítio Alostérico/efeitos dos fármacos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Niacinamida/análogos & derivados , Pirazóis/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Domínio Catalítico/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dasatinibe/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Quimioterapia Combinada , Proteínas de Fusão bcr-abl/química , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Camundongos , Mutação , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Chem Inf Model ; 56(10): 2042-2052, 2016 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-27602694

RESUMO

We present three in silico volume of distribution at steady state (VDss) models generated on a training set comprising 1096 compounds, which goes well beyond the conventional drug space delineated by the Rule of 5 or similar approaches. We have performed a careful selection of descriptors and kept a homogeneous Molecular Interaction Field-based descriptor set and linear (Partial Least Squares, PLS) and nonlinear (Random Forest, RF) models. We have tested the models, which we deem orthogonal in nature due to different descriptors and statistical approaches, with good results. In particular we tested the RF model, via a leave-class-out approach and by using a set of 34 additional compounds not used for training. We report comparable results against in vivo scaling approaches with geometric mean-fold error at or below 2 (for a set of 60 compounds with animal data available) and discuss the predictive performance based on the ionization states of the compounds. Lastly, we report the findings using a two-tier approach (classification followed by regression) based on VDss ranges, in an attempt to improve the prediction of compounds with very high VDss. We would recommend, overall, the RF model, with 33 descriptors, as the primary choice for VDss prediction in humans.


Assuntos
Simulação por Computador , Descoberta de Drogas/métodos , Modelos Biológicos , Preparações Farmacêuticas/química , Farmacocinética , Animais , Humanos , Modelos Lineares
9.
J Med Chem ; 59(14): 6920-8, 2016 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-27355833

RESUMO

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) provided access to analogues in the Northern region (C2-C10). Selective hydrolysis of the C10 amide of lead compound 2 and subsequent derivatization led to novel carbon- and nitrogen-linked analogues (e.g., 3) which improved antibacterial potency across a panel of Gram-positive organisms. In addition, congeners with improved physicochemical properties were identified which proved efficacious in murine sepsis and hamster C. difficile models of disease. Optimal efficacy in the hamster model of C. difficile was achieved with compounds that possessed both potent antibacterial activity and high aqueous solubility.


Assuntos
Antibacterianos/farmacologia , Infecções por Clostridium/tratamento farmacológico , Clostridium difficile/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Tiazóis/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Cricetinae , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Solubilidade , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
10.
J Med Chem ; 59(17): 7773-82, 2016 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-27347692

RESUMO

SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein-ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.


Assuntos
Antineoplásicos/química , Piperidinas/química , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Pirazinas/química , Pirimidinas/química , Administração Oral , Regulação Alostérica , Sítio Alostérico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Drogas , Feminino , Xenoenxertos , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Nus , Modelos Moleculares , Transplante de Neoplasias , Piperidinas/síntese química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Conformação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 11/química , Pirazinas/síntese química , Pirazinas/farmacocinética , Pirazinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Relação Estrutura-Atividade
11.
J Pharm Sci ; 105(3): 1277-87, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26886320

RESUMO

We present a systematic evaluation of the Wajima superpositioning method to estimate the human intravenous (i.v.) pharmacokinetic (PK) profile based on a set of 54 marketed drugs with diverse structure and range of physicochemical properties. We illustrate the use of average of "best methods" for the prediction of clearance (CL) and volume of distribution at steady state (VDss) as described in our earlier work (Lombardo F, Waters NJ, Argikar UA, et al. J Clin Pharmacol. 2013;53(2):178-191; Lombardo F, Waters NJ, Argikar UA, et al. J Clin Pharmacol. 2013;53(2):167-177). These methods provided much more accurate prediction of human PK parameters, yielding 88% and 70% of the prediction within 2-fold error for VDss and CL, respectively. The prediction of human i.v. profile using Wajima superpositioning of rat, dog, and monkey time-concentration profiles was tested against the observed human i.v. PK using fold error statistics. The results showed that 63% of the compounds yielded a geometric mean of fold error below 2-fold, and an additional 19% yielded a geometric mean of fold error between 2- and 3-fold, leaving only 18% of the compounds with a relatively poor prediction. Our results showed that good superposition was observed in any case, demonstrating the predictive value of the Wajima approach, and that the cause of poor prediction of human i.v. profile was mainly due to the poorly predicted CL value, while VDss prediction had a minor impact on the accuracy of human i.v. profile prediction.


Assuntos
Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/metabolismo , Administração Intravenosa/métodos , Animais , Cães , Haplorrinos , Humanos , Ratos , Análise de Regressão , Especificidade da Espécie
12.
J Chem Inf Model ; 55(7): 1449-59, 2015 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-26052622

RESUMO

The ionization state of drugs influences many pharmaceutical properties such as their solubility, permeability, and biological activity. It is therefore important to understand the structure property relationship for the acid-base dissociation constant pKa during the lead optimization process to make better-informed design decisions. Computational approaches, such as implemented in MoKa, can help with this; however, they often predict with too large error especially for proprietary compounds. In this contribution, we look at how retraining helps to greatly improve prediction error. Using a longitudinal study with data measured over 15 years in a drug discovery environment, we assess the impact of model training on prediction accuracy and look at model degradation over time. Using the MoKa software, we will demonstrate that regular retraining is required to address changes in chemical space leading to model degradation over six to nine months.


Assuntos
Fenômenos Químicos , Aprendizado de Máquina , Modelos Teóricos , Reprodutibilidade dos Testes
13.
J Med Chem ; 57(10): 4397-405, 2014 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-24773013

RESUMO

We introduce a two-tier model based on an exhaustive data set, where discriminant models based on principal component analysis (PCA) and partial least squares (PLS) are used separately and in conjunction, and we show that PCA is highly discriminant approaching 95% accuracy in the assignment of the primary clearance mechanism. Furthermore, the PLS model achieved a quantitative predictive performance comparable to methods based on scaling of animal data while not requiring the use of either in vivo or in vitro data, thus sparing the use of animal. This is likely the highest performance that can be expected from a computational approach, and further improvements may be difficult to reach. We further offer the medicinal scientist a PCA model to guide in vitro and/or in vivo studies to help limit the use of resources via very rapid computations.


Assuntos
Simulação por Computador , Taxa de Depuração Metabólica , Análise de Componente Principal , Animais , Haplorrinos , Humanos , Análise dos Mínimos Quadrados
14.
J Clin Pharmacol ; 53(2): 167-77, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23436262

RESUMO

The authors present a comprehensive analysis on the estimation of volume of distribution at steady state (VD(ss) ) in human based on rat, dog, and monkey data on nearly 400 compounds for which there are also associated human data. This data set, to the authors- knowledge, is the largest publicly available, has been carefully compiled from literature reports, and was expanded with some in-house determinations such as plasma protein binding data. This work offers a good statistical basis for the evaluation of applicable prediction methods, their accuracy, and some methods-dependent diagnostic tools. The authors also grouped the compounds according to their charge classes and show the applicability of each method considered to each class, offering further insight into the probability of a successful prediction. Furthermore, they found that the use of fraction unbound in plasma, to obtain unbound volume of distribution, is generally detrimental to accuracy of several methods, and they discuss possible reasons. Overall, the approach using dog and monkey data in the íie-Tozer equation offers the highest probability of success, with an intrinsic diagnostic tool based on aberrant values (<0 or >1) for the calculated fraction unbound in tissue. Alternatively, methods based on dog data (single-species scaling) and rat and dog data (íie-Tozer equation with 2 species or multiple regression methods) may be considered reasonable approaches while not requiring data in nonhuman primates.


Assuntos
Avaliação Pré-Clínica de Medicamentos , Farmacocinética , Animais , Cães , Haplorrinos , Humanos , Ratos , Especificidade da Espécie , Distribuição Tecidual
15.
J Clin Pharmacol ; 53(2): 178-91, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23436263

RESUMO

A comprehensive analysis on the prediction of human clearance based on intravenous pharmacokinetic data from rat, dog, and monkey for approximately 400 compounds was undertaken. This data set has been carefully compiled from literature reports and expanded with some in-house determinations for plasma protein binding and rat clearance. To the authors- knowledge, this is the largest publicly available data set. The present examination offers a comparison of 37 different methods for prediction of human clearance across compounds of diverse physicochemical properties. Furthermore, this work demonstrates the application of each prediction method to each charge class of the compounds, thus presenting an additional dimension to prediction of human pharmacokinetics. In general, the observations suggest that methods employing monkey clearance values and a method incorporating differences in plasma protein binding between rat and human yield the best overall predictions as suggested by approximately 60% compounds within 2-fold geometric mean-fold error. Other single-species scaling or proportionality methods incorporating the fraction unbound in the corresponding preclinical species for prediction of free clearance in human were generally unsuccessful.


Assuntos
Avaliação Pré-Clínica de Medicamentos , Farmacocinética , Animais , Cães , Haplorrinos , Humanos , Taxa de Depuração Metabólica , Ratos , Especificidade da Espécie
16.
Drug Metab Dispos ; 40(11): 2074-80, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22851614

RESUMO

In vitro metabolite identification and GSH trapping studies in human liver microsomes were conducted to understand the bioactivation potential of compound 1 [2-(6-(4-(4-(2,4-difluorobenzyl)phthalazin-1-yl)piperazin-1-yl)pyridin-3-yl)propan-2-ol], an inhibitor of the Hedgehog pathway. The results revealed the formation of a unique, stable quinone methide metabolite (M1) via ipso substitution of a fluorine atom and subsequent formation of a GSH adduct (M2). The stability of this metabolite arises from extensive resonance-stabilized conjugation of the substituted benzylphthalazine moiety. Cytochrome P450 (P450) phenotyping studies revealed that the formation of M1 and M2 were NADPH-dependent and primarily catalyzed by CYP3A4 among the studied P450 isoforms. In summary, an unusual and stable quinone methide metabolite of compound 1 was identified, and a mechanism was proposed for its formation via an oxidative ipso substitution.


Assuntos
Glutationa/metabolismo , Proteínas Hedgehog/antagonistas & inibidores , Indolquinonas/farmacocinética , Ftalazinas/farmacocinética , Compostos de Benzil/farmacocinética , Compostos de Benzil/farmacologia , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Proteínas Hedgehog/metabolismo , Humanos , Indolquinonas/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , NADP/metabolismo , Oxirredução , Ftalazinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas por Ionização por Electrospray/métodos
17.
J Chem Inf Model ; 52(8): 2069-78, 2012 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-22715914

RESUMO

The prediction of the total human plasma clearance of novel chemical entities continues to be of paramount importance in drug design and optimization, because it impacts both dose size and dose regimen. Although many in vivo and in vitro methods have been proposed, a well-constructed, well-validated, and less resource-intensive computational tool would still be very useful in an iterative compound design cycle. A new completely in silico linear PLS (partial least-squares) model to predict the human plasma clearance was built on the basis of a large data set of 754 compounds using physicochemical descriptors and structural fragments, the latter able to better represent biotransformation processes. The model has been validated using the "ELASTICO" approach (Enhanced Leave Analog-Structural, Therapeutic, Ionization Class Out) based on ten therapeutic/structural analog classes. The model yields a geometric mean fold error (GMFE) of 2.1 and a percentage of compounds predicted within 2- and 3-fold error of 59% and 80%, respectively, showing an improved performance when compared with previous published works in predicting clearance of neutral compounds, and a very good performance with ionized molecules at pH 7.5, able to compare favorably with fairly accurate in vivo methods.


Assuntos
Biologia Computacional/métodos , Preparações Farmacêuticas/sangue , Animais , Fenômenos Químicos , Cães , Humanos , Análise dos Mínimos Quadrados , Modelos Lineares , Taxa de Depuração Metabólica , Preparações Farmacêuticas/química , Ratos
18.
J Med Chem ; 54(13): 4752-72, 2011 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-21650221

RESUMO

Histone deacetylase (HDAC) inhibitors have shown promise in treating various forms of cancer. However, many HDAC inhibitors from diverse structural classes have been associated with QT prolongation in humans. Inhibition of the human ether a-go-go related gene (hERG) channel has been associated with QT prolongation and fatal arrhythmias. To determine if the observed cardiac effects of HDAC inhibitors in humans is due to hERG blockade, a highly potent HDAC inhibitor devoid of hERG activity was required. Starting with dacinostat (LAQ824), a highly potent HDAC inhibitor, we explored the SAR to determine the pharmacophores required for HDAC and hERG inhibition. We disclose here the results of these efforts where a high degree of pharmacophore homology between these two targets was discovered. This similarity prevented traditional strategies for mitigating hERG binding/modulation from being successful and novel approaches for reducing hERG inhibition were required. Using a hERG homology model, two compounds, 11r and 25i, were discovered to be highly efficacious with weak affinity for the hERG and other ion channels.


Assuntos
Acrilamidas/toxicidade , Antineoplásicos/toxicidade , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Inibidores de Histona Desacetilases/toxicidade , Ácidos Hidroxâmicos/toxicidade , Acrilamidas/síntese química , Acrilamidas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Canal de Potássio ERG1 , Células HCT116 , Meia-Vida , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Técnicas In Vitro , Camundongos , Camundongos Nus , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Transplante de Neoplasias , Técnicas de Patch-Clamp , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição Tecidual , Transplante Heterólogo
19.
Drug Metab Dispos ; 38(7): 1159-65, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20375179

RESUMO

Volume of distribution (VD) is a key pharmacokinetic property that together with clearance determines the half-life or residence time of drug in the body. It is commonly expressed as steady-state volume of distribution VD(ss) with a physiological basis for its understanding developed by Øie and Tozer in 1979. The Øie-Tozer equation uses terms for plasma protein binding (f(up)), tissue binding (f(ut)), and the extravascular/intravascular ratio of albumin as well as constants for the volumes of plasma, extracellular fluid, and tissue. We explored this model using a data set of 553 drugs for which VD(ss) and plasma protein binding were available in humans. Eighteen percent of cases (102 compounds) did not obey the Øie-Tozer model, with the rearranged equation giving an aberrant f(ut) value (f(ut) < 0 or f(ut) > 1), in particular for compounds with VD(ss) < 0.6 l/kg and f(up) > 0.1. Further analysis of this group of compounds revealed patterns in physicochemical attributes with a high proportion exemplified by logP less than 0 (i.e., very hydrophilic), polar surface area >150 A(2), and a difference between logP and logD >2.5. In addition there was a high representation of certain drug classes including anti-infectives as well as neuromuscular blockers and contrast agents. The majority of compounds were also found to have literature evidence, implicating active transport processes in their disposition. This analysis provides some important insights for pharmacokinetic optimization in this particular chemical space, as well as in the application of the Øie-Tozer model for predicting volume of distribution in humans.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Preparações Farmacêuticas/metabolismo , Fenômenos Químicos , Previsões/métodos , Humanos , Modelos Biológicos , Preparações Farmacêuticas/química , Distribuição Tecidual
20.
J Med Chem ; 52(14): 4488-95, 2009 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-19603833

RESUMO

The prediction of human pharmacokinetics early in the drug discovery cycle has become of paramount importance, aiding candidate selection and benefit-risk assessment. We present herein computational models to predict human volume of distribution at steady state (VD(ss)) entirely from in silico structural descriptors. Using both linear and nonlinear statistical techniques, partial least-squares (PLS), and random forest (RF) modeling, a data set of human VD(ss) values for 669 drug compounds recently published ( Drug Metab. Disp. 2008 , 36 , 1385 - 1405 ) was explored. Descriptors covering 2D and 3D molecular topology, electronics, and physical properties were calculated using MOE and Volsurf+. Model evaluation was accomplished using a leave-class-out approach on nine therapeutic or structural classes. The models were assessed using an external test set of 29 additional compounds. Our analysis generated models, both via a single method or consensus which were able to predict human VD(ss) within geometric mean 2-fold error, a predictive accuracy considered good even for more resource-intensive approaches such as those requiring data generated from studies in multiple animal species.


Assuntos
Biologia Computacional , Dinâmica não Linear , Farmacocinética , Humanos , Análise dos Mínimos Quadrados , Modelos Lineares , Análise de Componente Principal
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