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1.
Bioorg Med Chem Lett ; 73: 128891, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35842205

RESUMO

TYK2 is a member of the JAK family of kinases and a key mediator of IL-12, IL-23, and type I interferon signaling. These cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genetic association studies, TYK2 inhibition is an attractive therapeutic strategy for these diseases. Herein, we report the discovery of a series of highly selective catalytic site TYK2 inhibitors designed using FEP+ and structurally enabled design starting from a virtual screen hit. We highlight the structure-based optimization to identify a lead candidate 30, a potent cellular TYK2 inhibitor with excellent selectivity, pharmacokinetic properties, and in vivo efficacy in a mouse psoriasis model.


Assuntos
Psoríase , TYK2 Quinase , Animais , Humanos , Janus Quinases , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Psoríase/tratamento farmacológico , Roedores
2.
Chemistry ; 16(31): 9555-62, 2010 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-20623567

RESUMO

The development and application of chiral, non-racemic Re(V)-oxo complexes to the enantioselective reduction of prochiral ketones is described. In addition to the enantioselective reduction of prochiral ketones, we report the application of these complexes to 1) a tandem Meyer-Schuster rearrangement/reduction to access enantioenriched allylic alcohols and 2) the enantioselective reduction of imines.


Assuntos
Cianetos/química , Iminas/química , Cetonas/química , Catálise , Estrutura Molecular , Oxirredução , Estereoisomerismo
3.
Org Lett ; 5(22): 4113-5, 2003 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-14572262

RESUMO

[reaction: see text]. An asymmetric approach toward the [6-7] ring system of the guanacastepenes is described.


Assuntos
Diterpenos/síntese química , Cristalografia por Raios X , Ciclização , Furanos/química , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estrutura Molecular , Compostos Policíclicos/química
4.
Org Lett ; 6(8): 1325-7, 2004 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-15070328

RESUMO

A mild aromatic propargylation reaction, employing an air- and moisture-tolerant rhenium-oxo complex ((dppm)ReOCl(3)) as a catalyst and a propargyl alcohol as the electrophile, is described. The reaction tolerates a broad range of functional groups and regioselectively affords propargylic arenas without formation of the isomeric allenyl adducts. The potential of this rhenium(V)-catalyzed reaction is exemplified by application of the propargylation to the synthesis of O-methyldetrol, mimosifoliol, and beta-apopicropodophyllin. [reaction: see text]

5.
J Med Chem ; 57(6): 2683-91, 2014 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-24520947

RESUMO

Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. Select pharmacokinetic and in vivo efficacy data are presented.


Assuntos
Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridazinas/síntese química , Piridazinas/farmacologia , Baço/enzimologia , Amidas/síntese química , Amidas/farmacologia , Animais , Biologia Computacional , Simulação por Computador , Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Conformação Molecular , Mutagênese/efeitos dos fármacos , Testes de Mutagenicidade , Inibidores de Proteínas Quinases/farmacocinética , Piridazinas/farmacocinética , Ratos , Baço/efeitos dos fármacos , Relação Estrutura-Atividade , Difração de Raios X
6.
J Med Chem ; 56(4): 1677-92, 2013 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-23350847

RESUMO

We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazinas/síntese química , Pirróis/síntese química , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/enzimologia , Proteínas Sanguíneas/metabolismo , Cristalografia por Raios X , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Pirazinas/farmacologia , Pirazinas/toxicidade , Pirróis/farmacologia , Pirróis/toxicidade , Relação Estrutura-Atividade , Quinase Syk
10.
ChemMedChem ; 4(1): 88-99, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19006142

RESUMO

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are part of the preferred treatment regimens for individuals infected with HIV. These NNRTI-based regimens are efficacious, but the most popular NNRTIs have a low genetic barrier to resistance and have been associated with adverse events. There is therefore still a need for efficacious antiviral medicines that facilitate patient adherence and allow durable suppression of viral replication. As part of an extensive program targeted toward the discovery of NNRTIs that have favorable pharmacokinetic properties, good potency against NNRTI-resistant viruses, and a high genetic barrier to drug resistance, we focused on the optimization of a series of diaryl ether NNRTIs. In the course of this effort, we employed molecular modeling to design a new set of NNRTIs that that are active against wild-type HIV and key NNRTI-resistant mutant viruses. The structure-activity relationships observed in this series of compounds provide insight into the structural features required for NNRTIs that inhibit the replication of a wide range of mutant viruses. Selected compounds have promising pharmacokinetic profiles.


Assuntos
Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/química , Éteres Fenílicos/química , Éteres Fenílicos/farmacologia , Inibidores da Transcriptase Reversa/química , Animais , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Simulação por Computador , Cães , Desenho de Fármacos , Farmacorresistência Viral/genética , HIV/genética , Transcriptase Reversa do HIV/antagonistas & inibidores , Concentração Inibidora 50 , Modelos Moleculares , Mutação , Éteres Fenílicos/farmacocinética , Ratos , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade
11.
J Med Chem ; 51(23): 7449-58, 2008 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-19007201

RESUMO

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are recommended components of preferred combination antiretroviral therapies used for the treatment of HIV. These regimens are extremely effective in suppressing virus replication. Structure-based optimization of diaryl ether inhibitors led to the discovery of a new series of pyrazolo[3,4-c]pyridazine NNRTIs that bind the reverse transcriptase enzyme of human immunodeficiency virus-1 (HIV-RT) in an expanded volume relative to most other inhibitors in this class.The binding mode maintains the beta13 and beta14 strands bearing Pro236 in a position similar to that in the unliganded reverse transcriptase structure, and the distribution of interactions creates the opportunity for substantial resilience to single point mutations. Several pyrazolopyridazine NNRTIs were found to be highly effective against wild-type and NNRTI-resistant viral strains in cell culture.


Assuntos
Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , Pirazóis/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Sítios de Ligação , Linhagem Celular Transformada , Cristalografia por Raios X , Cães , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Haplorrinos , Humanos , Ligação de Hidrogênio , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Ratos , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Estereoisomerismo , Relação Estrutura-Atividade
12.
J Am Chem Soc ; 128(51): 17057-62, 2006 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-17177458

RESUMO

A concise, stereoselective, and convergent total synthesis of the unnatural enantiomer of the neodolastane diterpenoid heptemerone B has been completed. Saponification of (-)-heptemerone afforded (-)-guanacastepene E. The absolute stereochemistry of (-)-heptemerone B was thus established as 5-(S), the same as (-)-guanacastepene E. The longest linear sequence of the synthesis comprises 17 (18) steps from simple known starting materials. Our general synthetic approach integrates a diverse set of reactions, including an intramolecular Heck reaction to create one quaternary stereocenter and a cuprate conjugate addition for the establishment of the other. The central seven-membered ring was closed with an uncommon electrochemical oxidation, whereas the five-membered ring was formed through ring-closing metathesis. The absolute configuration of the two key building blocks was established through an asymmetric reduction and an asymmetric ene reaction.


Assuntos
Diterpenos/síntese química , Ciclização , Diterpenos/química , Modelos Moleculares , Estrutura Molecular , Oxirredução , Estereoisomerismo
13.
J Am Chem Soc ; 125(14): 4056-7, 2003 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-12670220

RESUMO

The metal-oxygen bond plays a critical role in some of the most important biological and synthetic reactions. However, the majority of these processes result in the oxidation of the target organic substrate; applications of this class of metal complexes to other organic transformations are extremely rare. In this paper, we report a new type of catalytic process in which complexes with metal-oxygen multiple bonds are used as reductants rather than oxidants. The overall reaction provides a highly chemoselective reduction/protection of carbonyl groups. In addition to providing a new way of catalyzing organic reactions, these catalysts can be used in the presence of a wide range of other functional groups such as amino, cyano, nitro, aryl halo, ester, and alkene; unlike many of their late metal relatives, they are inexpensive as well as air and moisture tolerant.

14.
J Am Chem Soc ; 126(14): 4526-7, 2004 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-15070364

RESUMO

The intramolecular addition of beta-ketoesters to unactivated alkynes under neutral conditions and at room temperature is described. The method employs triphenylphosphinegold(I) cation as a catalyst for the formation of exo-methylenecycloalkanes. Both monocyclic and bicyclic cyclopentanes and cyclohexanes can be formed in excellent yields and with good diastereoselectivity.

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