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1.
ACS Med Chem Lett ; 15(10): 1787-1794, 2024 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-39411537

RESUMEN

The science of drug discovery involves multiparameter optimization of molecular structures through iterative design-make-test cycles. For medicinal chemistry library synthesis, traditional workflows involve the isolation of each individual compound, gravimetric quantitation, and preparation of a standard concentration solution for biological assays. In this work, we explore ways to expedite this process by testing unpurified library mixtures using a combination of mass spectrometry-based assays for affinity selection and microsomal metabolic stability. Utilizing this approach, microgram quantities of crude library mixtures can be used to identify high affinity, metabolically stable library members for isolation and full characterization. This streamlined approach was demonstrated for the synthesis and evaluation of two libraries of histone deacetylase inhibitors and was shown to generate decision-making data in line with traditional workflows. The advantages of this paradigm include greatly reduced cycle time, reduced material requirements, and concentration of resources on the most promising compounds.

2.
J Chem Inf Model ; 62(14): 3275-3280, 2022 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-35796226

RESUMEN

As with many other institutions, our company maintains many quantitative structure-activity relationship (QSAR) models of absorption, distribution, metabolism, excretion, and toxicity (ADMET) end points and updates the models regularly. We recently examined version-to-version predictivity for these models over a period of 10 years. In this approach we monitor the goodness of prediction of new molecules relative to the training set of model version V before they are incorporated in the updated model V+1. Using a cell-based permeability assay (Papp) as an example, we illustrate how the QSAR models made from this data are generally predictive and can be utilized to enrich chemical designs and synthesis. Despite the obvious utility of these models, we turned up unexpected behavior in Papp and other ADMET activities for which the explanation is not obvious. One such behavior is that the apparent predictivity of the models as measured by root-mean-square-error can vary greatly from version to version and is sometimes very poor. One intuitively appealing explanation is that the observed activities of the new molecules fall outside the bulk of activities in the training set. Alternatively, one may think that the new molecules are exploring different regions of chemical space than the training set. However, the real explanation has to do with activity cliffs. If the observed activities of the new molecules are different than expected based on similar molecules in the training set, the predictions will be less accurate. This is true for all our ADMET end points.


Asunto(s)
Relación Estructura-Actividad Cuantitativa
3.
J Chem Inf Model ; 60(4): 1969-1982, 2020 04 27.
Artículo en Inglés | MEDLINE | ID: mdl-32207612

RESUMEN

Given a particular descriptor/method combination, some quantitative structure-activity relationship (QSAR) datasets are very predictive by random-split cross-validation while others are not. Recent literature in modelability suggests that the limiting issue for predictivity is in the data, not the QSAR methodology, and the limits are due to activity cliffs. Here, we investigate, on in-house data, the relative usefulness of experimental error, distribution of the activities, and activity cliff metrics in determining how predictive a dataset is likely to be. We include unmodified in-house datasets, datasets that should be perfectly predictive based only on the chemical structure, datasets where the distribution of activities is manipulated, and datasets that include a known amount of added noise. We find that activity cliff metrics determine predictivity better than the other metrics we investigated, whatever the type of dataset, consistent with the modelability literature. However, such metrics cannot distinguish real activity cliffs due to large uncertainties in the activities. We also show that a number of modern QSAR methods, and some alternative descriptors, are equally bad at predicting the activities of compounds on activity cliffs, consistent with the assumptions behind "modelability." Finally, we relate time-split predictivity with random-split predictivity and show that different coverages of chemical space are at least as important as uncertainty in activity and/or activity cliffs in limiting predictivity.


Asunto(s)
Relación Estructura-Actividad Cuantitativa , Error Científico Experimental , Relación Estructura-Actividad , Incertidumbre
4.
ACS Med Chem Lett ; 5(2): 124-7, 2014 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-24900784

RESUMEN

The development of small-molecule MDM2 inhibitors to restore dysfunctional p53 activities represents a novel approach for cancer treatment. In a previous communication, the efforts leading to the identification of a non-imidazoline MDM2 inhibitor, RG7388, was disclosed and revealed the desirable in vitro and in vivo pharmacological properties that this class of pyrrolidine-based inhibitors possesses. Given this richness and the critical need for a wide variety of chemical structures to ensure success in the clinic, research was expanded to evaluate additional derivatives. Here we report two new potent, selective, and orally active p53-MDM2 antagonists, RO5353 and RO2468, as follow-ups with promising potential for clinical development.

5.
Bioorg Med Chem Lett ; 21(21): 6485-90, 2011 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-21925881

RESUMEN

The discovery of potent N-hydroxyl caprolactam matrix metalloproteinase (MMP) inhibitors (6) based on the natural product Cobactin-T (2) is described. The synthetic method, which utilizes the ring closing metathesis reaction, is compatible to provide complementary (R) and (S) enantiomers. These compounds tested against MMP-2 and 9, show that the R stereochemistry (i.e., 16), which is opposite for that found in the natural product Cobactin-T is >1000-fold more active with IC(50) values of 0.2-0.6nM against both enzymes. The variation in the incorporation of the sulfonamide enzyme recognition element (Ar(2)XAr(1)SO(2)N(R(1)), 6), along with alterations in the RCM/double bond chemistry (R(2)) provided a series of sub nanomolar MMP inhibitors. For example, compounds 16 and 34 were found to be the most potent with IC(50) values against MMP-2 and MMP-9 found to be between 0.2 and 0.6nM with 34 being the most potent compound discovered (MMP-2 IC(50)=0.39nM and MMP-9 IC(50)=0.22nM). Compounds 16 and 34 showed acceptable drug-like properties in vivo with compound 34 showing oral bioavailability.


Asunto(s)
Azepinas/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/farmacología , Azepinas/farmacocinética , Disponibilidad Biológica , Ciclización , Descubrimiento de Drogas , Concentración 50 Inhibidora , Inhibidores de Proteasas/farmacocinética , Estereoisomerismo
8.
Bioorg Med Chem Lett ; 18(3): 1135-9, 2008 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-18086526

RESUMEN

A new series of beta-N-biaryl ether sulfonamide hydroxamates as novel gelatinase inhibitors is described. These compounds exhibit good potency for MMP-2 and MMP-9 without inhibiting MMP-1. The structure-activity relationships (SAR) reveal the biaryl ether type P1' moiety together with methanesulfonamide is the optimal combination that provides inhibitory activity of MMP-9 in the single-digit nanomolar range.


Asunto(s)
Gelatinasas/antagonistas & inhibidores , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , Pirazinas/síntesis química , Pirazinas/farmacología , Animales , Diseño de Fármacos , Humanos , Ácidos Hidroxámicos/química , Microsomas Hepáticos/efectos de los fármacos , Estructura Molecular , Pirazinas/química , Ratas , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacología
9.
Bioorg Med Chem Lett ; 18(1): 409-13, 2008 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-17981034

RESUMEN

Matrix metalloproteinase-9 (MMP-9) has been implicated in the breakdown of the blood-brain barrier during cerebral ischemia. As a result, inhibition of MMP-9 may have utility as a therapeutic intervention in stroke. Towards this end, we have synthesized a series of 1-hydroxy-2-pyridinones that have excellent in vitro potency in inhibiting MMP-9 in addition to MMP-2. Representative compounds also demonstrate good efficacy in the mouse transient mid-cerebral artery occlusion (tMCAO) model of cerebral ischemia.


Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/síntesis química , Piridonas/síntesis química , Piridonas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Modelos Animales de Enfermedad , Concentración 50 Inhibidora , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Piridonas/química , Piridonas/farmacocinética , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Zinc/química , Zinc/metabolismo
10.
Bioorg Med Chem Lett ; 18(3): 1140-5, 2008 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-18083558

RESUMEN

The introduction and the optimization of an alpha-amino substituent based on a series of alpha-hydroxy-beta-N-biaryl ether sulfonamide hydroxamates is described. The modification leads to a new series of MMP-2/MMP-9 inhibitors with enhanced inhibitory activities and improved ADME properties. An efficacy study on reducing the ischemia-induced brain edema in the rat transient middle cerebral artery occlusion (tMCAo) model is also demonstrated.


Asunto(s)
Aminoácidos/química , Gelatinasas/antagonistas & inhibidores , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , Pirazinas/síntesis química , Pirazinas/farmacología , Animales , Edema Encefálico/inducido químicamente , Modelos Animales de Enfermedad , Diseño de Fármacos , Humanos , Ácidos Hidroxámicos/química , Microsomas Hepáticos/efectos de los fármacos , Arteria Cerebral Media/efectos de los fármacos , Estructura Molecular , Pirazinas/química , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacología
13.
J Biomol Screen ; 9(8): 678-86, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15634794

RESUMEN

The past approach of high-throughput screening of everything in the corporate collection has been shown to be very expensive in terms of reagents cost, disposal cost, and compound collection depletion. It is well known that screening campaigns produce several hits, of which only 50% confirm on average. More efficient ways of screening can provide an informative structure-activity relationship (SAR), which in turn can be used to build mathematical models for further probing the activity space and directing chemical synthesis. The authors report new methods and insights to extract the maximum possible information from a screening experiment and find most of the possible hits in the corporate collection while screening as few compounds as possible.


Asunto(s)
Técnicas Químicas Combinatorias , Biología Computacional , Evaluación Preclínica de Medicamentos/métodos , Análisis por Conglomerados , Simulación por Computador , Modelos Químicos , Relación Estructura-Actividad Cuantitativa , Relación Estructura-Actividad
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