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1.
Bioorg Med Chem Lett ; : 126604, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31445854

RESUMO

This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9. These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency.

2.
SLAS Technol ; 23(5): 412-422, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30016131

RESUMO

We describe a custom Internet of Things (IoT) device used for tracking barcoded containers end to end in a high-throughput analysis and purification laboratory. Our IoT device fills an important gap that previously prevented us from fully tracking barcoded sample containers through manual steps in a multistep workflow, such as when samples are "parked" for temporary storage, or when using instrumentation not otherwise equipped with barcode scanners, a common occurrence found with specific centrifugal evaporation instruments. The custom device reads container barcodes and sends a small amount of data to our back-end data systems. Once data have been received and processed, users are alerted to any system responses via aural and visual feedback. Components of the IoT system include a low-cost headless IoT computer, a barcode reader, and a multicolor LED strip. We believe that the model for our device will facilitate simple and rapid deployment of IoT to the broader laboratory community. All source code and device configurations will be released into the public domain and made freely available.

3.
J Org Chem ; 83(8): 4323-4335, 2018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29537839

RESUMO

Macrocyclic peptides containing N-alkylated amino acids have emerged as a promising therapeutic modality, capable of modulating protein-protein interactions and an intracellular delivery of hydrophilic payloads. While multichannel automated solid-phase peptide synthesis (SPPS) is a practical approach for peptide synthesis, the requirement for slow and inefficient chromatographic purification of the product peptides is a significant limitation to exploring these novel compounds. Herein, we invent a "catch-release" strategy for the nonchromatographic purification of macrocyclic peptides. A traceless catch process is enabled by the invention of a dual-functionalized N-terminal acetate analogue, which serves as a handle for capture onto a purification resin and as a leaving group for macrocyclization. Displacement by a C-terminal nucleophilic side chain thus releases the desired macrocycle from the purification resin. By design, this catch/release process is a logic test for the presence of the key components required for cyclization, thus removing impurities which lack the required functionality, such as common classes of peptide impurities, including hydrolysis fragments and truncated sequences. The method was shown to be highly effective with three libraries of macrocyclic peptides, containing macrocycles of 5-20 amino acids, with either thioether- or amine-based macrocyclic linkages; in this latter class, the reported method represents an enabling technology. In all cases, the catch-release protocol afforded significant enrichment of the target peptides purity, in many cases completely obviating the need for chromatography. Importantly, we have adapted this process for automation on a standard multichannel peptide synthesizer, achieving an efficient and completely integrated synthesis and purification platform for the preparation of these important molecules.

4.
J Med Chem ; 60(4): 1417-1431, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28112924

RESUMO

A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding Ki and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both Gq-coupled intracellular Ca2+ flux and Gs-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.


Assuntos
Hipoglicemiantes/farmacologia , Pirrolidinas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Glicemia/análise , Glicemia/metabolismo , Linhagem Celular , Células Cultivadas , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Modelos Moleculares , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapêutico , Ratos , Receptores Acoplados a Proteínas-G/metabolismo
5.
Bioorg Med Chem Lett ; 24(24): 5721-5726, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25453808

RESUMO

A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.


Assuntos
Descoberta de Drogas , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/química , Pirróis/química , Administração Oral , Animais , Ensaio de Imunoadsorção Enzimática , Humanos , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Conformação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-Atividade , Distribuição Tecidual
7.
J Lab Autom ; 18(5): 391-403, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23603752

RESUMO

A systematic method for assembling and solving complex compound distribution problems is presented in detail. The method is based on a model problem that enumerates the mathematical equations and constraints describing a source container, liquid handler, and three types of destination containers involved in a set of compound distributions. One source container and one liquid handler are permitted in any given problem formulation, although any number of compound distributions may be specified. The relative importance of all distributions is expressed by assigning weights, which are factored into the final mathematical problem specification. A computer program was created that automatically assembles and solves a complete compound distribution problem given the parameters that describe the source container, liquid handler, and any number and type of compound distributions. Business rules are accommodated by adjusting weighting factors assigned to each distribution. An example problem, presented and explored in detail, demonstrates complex and nonintuitive solution behavior.


Assuntos
Automação Laboratorial/métodos , Ensaios de Triagem em Larga Escala/métodos , Manejo de Espécimes/métodos , Simulação por Computador , Software
9.
ACS Comb Sci ; 14(9): 520-6, 2012 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-22909004

RESUMO

The use of standardized lean manufacturing principles to improve drug discovery productivity is often thought to be at odds with fostering innovation. This manuscript describes how selective implementation of a lean optimized process, in this case centralized purification for medicinal chemistry, can improve operational productivity and increase scientist time available for innovation. A description of the centralized purification process is provided along with both operational and impact (productivity) metrics, which indicate lower cost, higher output, and presumably more free time for innovation as a result of the process changes described.


Assuntos
Descoberta de Drogas/economia , Preparações Farmacêuticas/economia , Preparações Farmacêuticas/isolamento & purificação , Química Farmacêutica/economia , Química Farmacêutica/métodos , Química Farmacêutica/organização & administração , Descoberta de Drogas/métodos , Descoberta de Drogas/organização & administração , Eficiência Organizacional , Humanos , Preparações Farmacêuticas/química
10.
J Med Chem ; 55(13): 6162-75, 2012 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-22650305

RESUMO

A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.


Assuntos
Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Estilbenos/química , Estilbenos/farmacologia , Animais , Anticolesterolemiantes/síntese química , Apolipoproteína B-100/antagonistas & inibidores , Apolipoproteína B-100/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Doença das Coronárias/tratamento farmacológico , Cricetinae , Descoberta de Drogas , Frequência Cardíaca/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Piridinas/síntese química , Ratos , Estilbenos/síntese química
14.
J Comb Chem ; 12(6): 877-82, 2010 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-20923153

RESUMO

Preparative HPLC and HPLC-MS are well established as the methods of choice for purification of pharmaceutical library compounds. Recent advances in supercritical fluid chromatography (SFC) have now made SFC a viable alternative to HPLC for this application. One of the potential arguments for using SFC in place of, or in addition to, HPLC is that it may offer different selectivity and thus has the potential for improved separation success rates. In this paper, we examine relative success rates for SFC and HPLC in obtaining adequate selectivity for successful separation. Our results suggest that use of SFC in addition to HPLC may result in a slight (1-2%) improvement in success rate compared to use of HPLC alone.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cromatografia com Fluido Supercrítico/métodos , Bibliotecas de Moléculas Pequenas/química , Desenho de Drogas
16.
Bioorg Med Chem Lett ; 18(11): 3168-72, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18485702

RESUMO

Several series of pyridine amides were identified as selective and potent 11beta-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH(2)SO(2), CH(2)S, CH(2)O, S, O, N, bond) between the distal aryl and central pyridyl groups are tolerated, and lipophilic amide groups are generally favored. On the distal aryl group, a number of substitutions are well tolerated. A crystal structure was obtained for a complex between 11beta-HSD1 and the most potent inhibitor in this series.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Amidas/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Desenho de Drogas , Humanos , Concentração Inibidora 50 , Conformação Molecular , Estrutura Molecular , Piridinas/química , Relação Estrutura-Atividade
18.
Bioorg Med Chem Lett ; 18(6): 1945-51, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18289854

RESUMO

An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compounds with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallography revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner.


Assuntos
Inibidores Enzimáticos/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirróis/química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Triazinas/química , Animais , Células CACO-2/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Glutationa Transferase/antagonistas & inibidores , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Conformação Proteica , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-met , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento/metabolismo , Neoplasias Gástricas/sangue , Neoplasias Gástricas/enzimologia , Relação Estrutura-Atividade
19.
20.
J Comb Chem ; 8(5): 664-9, 2006 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16961404

RESUMO

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.


Assuntos
Técnicas de Química Combinatória , Desenho de Drogas
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