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Bioorg Med Chem Lett ; 30(7): 126955, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32035698


This article describes the discovery of aryl hydroxy pyrimidinones and the medicinal chemistry efforts to optimize this chemotype for potent APJ agonism. APJ is a G-protein coupled receptor whose natural agonist peptide, apelin, displays hemodynamic improvement in the cardiac function of heart failure patients. A high throughput screen was undertaken to identify small molecule hits that could be optimized to mimic the apelin in vitro response. A potent and low molecular weight aryl hydroxy pyrimidinone analog 30 was identified through optimization of an HTS hit and medicinal chemistry efforts to improve its properties.

Cell ; 168(3): 527-541.e29, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-28111073


Advances in the synthesis and screening of small-molecule libraries have accelerated the discovery of chemical probes for studying biological processes. Still, only a small fraction of the human proteome has chemical ligands. Here, we describe a platform that marries fragment-based ligand discovery with quantitative chemical proteomics to map thousands of reversible small molecule-protein interactions directly in human cells, many of which can be site-specifically determined. We show that fragment hits can be advanced to furnish selective ligands that affect the activity of proteins heretofore lacking chemical probes. We further combine fragment-based chemical proteomics with phenotypic screening to identify small molecules that promote adipocyte differentiation by engaging the poorly characterized membrane protein PGRMC2. Fragment-based screening in human cells thus provides an extensive proteome-wide map of protein ligandability and facilitates the coordinated discovery of bioactive small molecules and their molecular targets.

Descoberta de Drogas/métodos , Proteômica/métodos , Adipócitos/citologia , Diferenciação Celular , Cristalografia por Raios X , Ensaios de Triagem em Larga Escala , Humanos , Hidrolases/química , Ligantes , Proteínas de Membrana/antagonistas & inibidores , Oxirredutases/química , Ligação Proteica , Receptores de Progesterona/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas
J Mol Biol ; 427(4): 924-942, 2015 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-25579995


The human pregnane X receptor (PXR) is a promiscuous nuclear receptor that functions as a sensor to a wide variety of xenobiotics and regulates expression of several drug metabolizing enzymes and transporters. We have generated "Adnectins", derived from 10th fibronectin type III domain ((10)Fn3), that target the PXR ligand binding domain (LBD) interactions with the steroid receptor co-activator-1 (SRC-1) peptide, displacing SRC-1 binding. Adnectins are structurally homologous to the immunoglobulin superfamily. Three different co-crystal structures of PXR LBD with Adnectin-1 and CCR1 (CC chemokine receptor-1) antagonist Compound-1 were determined. This structural information was used to modulate PXR affinity for a related CCR1 antagonist compound that entered into clinical trials for rheumatoid arthritis. The structures of PXR with Adnectin-1 reveal specificity of Adnectin-1 in not only targeting the interface of the SRC-1 interactions but also engaging the same set of residues that are involved in binding of SRC-1 to PXR. Substituting SRC-1 with Adnectin-1 does not alter the binding conformation of Compound-1 in the ligand binding pocket. The structure also reveals the possibility of using Adnectins as crystallization chaperones to generate structures of PXR with compounds of interest.

Coativador 1 de Receptor Nuclear/química , Receptores CCR1/antagonistas & inibidores , Receptores de Esteroides/química , Ureia/análogos & derivados , Valina/análogos & derivados , Sequência de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X , Humanos , Lignanas/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Receptor de Pregnano X , Ligação Proteica , Estrutura Terciária de Proteína , Receptores CCR1/metabolismo , Alinhamento de Sequência , Ressonância de Plasmônio de Superfície , Ureia/química , Ureia/metabolismo , Ureia/farmacologia , Valina/química , Valina/metabolismo , Valina/farmacologia
J Med Chem ; 55(22): 9643-53, 2012 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-23075267


A series of novel, potent CCR1 inhibitors was developed from a moderately active hit using an iterative parallel synthesis approach. The initial hit (composed of three subunits: an amine, a central amino acid, and an N-terminal cap) became the basis for a series of parallel chemical libraries designed to generate SAR data. Libraries were synthesized that explored each of the three subunits; the CCR1 binding data obtained revealed the following: (1) changes to the amine are not well tolerated; (2) small alkylamino acids are preferred in the center of the molecule; (3) substitutions at the N-terminus are generally well tolerated. These data were used to drive the optimization of the series, ultimately providing a lead with a CCR1 binding IC(50) of 28 nM (48). This lead demonstrates high selectivity for CCR1 over other CCR-family members, high microsomal stability, and good pharmacokinetics in mice.

Quimiotaxia/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Piperidinas/farmacologia , Receptores CCR/antagonistas & inibidores , Animais , Cálcio/metabolismo , Células Cultivadas , Humanos , Camundongos , Monócitos/citologia , Técnicas de Patch-Clamp , Piperidinas/síntese química , Piperidinas/farmacocinética , Ligação Proteica , Coelhos , Ratos , Receptores CCR/metabolismo , Relação Estrutura-Atividade , Distribuição Tecidual
J Comb Chem ; 8(5): 664-9, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16961404


The application of parallel synthesis to lead optimization programs in drug discovery has been an ongoing challenge since the first reports of library synthesis. A number of approaches to the application of parallel array synthesis to lead optimization have been attempted over the years, ranging from widespread deployment by (and support of) individual medicinal chemists to centralization as a service by an expert core team. This manuscript describes our experience with the latter approach, which was undertaken as part of a larger initiative to optimize drug discovery. In particular, we highlight how concepts taken from the manufacturing sector can be applied to drug discovery and parallel synthesis to improve the timeliness and thus the impact of arrays on drug discovery.

Técnicas de Química Combinatória , Desenho de Drogas