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1.
Sci Transl Med ; 11(502)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31341059

RESUMO

TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common autoimmune diseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of autoimmunity. BMS-986165 is a potent oral agent that similarly blocks receptor-stimulated activation of TYK2 allosterically and with high selectivity and potency afforded through optimized binding to a regulatory domain of the protein. Signaling and functional responses in human TH17, TH1, B cells, and myeloid cells integral to autoimmunity were blocked by BMS-986165, both in vitro and in vivo in a phase 1 clinical trial. BMS-986165 demonstrated robust efficacy, consistent with blockade of multiple autoimmune pathways, in murine models of lupus nephritis and inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases.

2.
J Am Chem Soc ; 131(1): 20-1, 2009 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-19072056

RESUMO

A new polymerization technique that allows for the first-ever synthesis of poly(phenylenedicyanovinylene)s (PPCN2Vs) is described. PPCN2Vs, with their high electron affinities and structural versatility, seem ideally suited to address the need for new n-type polymers. Remarkably the polymers presented herein become more photoluminescent, in the thin film, under continuous irradiation.


Assuntos
Polímeros/síntese química , Polivinil/síntese química , Ânions/química , Oxirredução
3.
Org Lett ; 10(6): 1291-4, 2008 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-18302397

RESUMO

Highly substituted, very hindered enones were synthesized using a two-step procedure that utilizes a diiodosamarium-promoted Reformatsky-type coupling and dehydration using Martin sulfurane. Both alpha-chloro- and alpha-bromoketones were coupled with a variety of carbonyl nucleophiles to form the intermediate beta-hydroxyketones, occurring with excellent diastereoselectivity, favoring the syn isomer (R1=Me). This technique complements other methods and enables the preparation of enones outside of the scope of current olefination methodology.


Assuntos
Samário/química , Estereoisomerismo
4.
Macromolecules ; 42(1): 452-454, 2008 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-20827441

RESUMO

The utility of Sato's titanium-mediated reduction of alkynes towards the synthesis of all cis-poly(phenylenevinylene)s (PPVs) is demonstrated by the syn-selective reduction of a variety of model diynes as well as a tetrayne. This technique was then applied to the reduction of a poly(phenyleneethynylene) (PPE) to provide the corresponding all-cis PPV polymer.

5.
J Org Chem ; 72(25): 9736-45, 2007 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-17985925

RESUMO

Synthetic studies toward the total synthesis of (+)-acutiphycin (1) resulted in the discovery of additive-free, highly regioselective nickel-catalyzed reductive coupling reactions of aldehydes and 1,6-enynes and the construction of an advanced intermediate in studies directed toward the synthesis of 1. Ultimately, although not employing the nickel-catalyzed reaction, a highly convergent total synthesis of (+)-acutiphycin featuring an intermolecular SmI2-mediated Reformatsky coupling reaction and macrolactonization initiated by a retro-ene reaction of an alkoxyalkyne was achieved. The resulting synthesis was 18 steps in the longest linear sequence from either methyl acetoacetate or isobutyraldehyde.


Assuntos
Compostos Heterocíclicos/síntese química , Macrolídeos/síntese química , Catálise , Cristalografia por Raios X , Compostos Heterocíclicos/química , Macrolídeos/química , Modelos Moleculares , Estrutura Molecular , Níquel/química , Estereoisomerismo
6.
Chem Commun (Camb) ; (43): 4441-9, 2007 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-17971951

RESUMO

Nickel-catalysed reductive coupling reactions of alkynes have emerged as powerful synthetic tools for the selective preparation of functionalized alkenes. One of the greatest challenges associated with these transformations is control of regioselectivity. Recent work from our laboratory has provided an improved understanding of several of the factors governing regioselectivity in these reactions, and related studies have revealed that the reaction mechanism can differ substantially depending on the ligand employed. A discussion of stereoselective transformations and novel applications of nickel catalysis in coupling reactions of alkynes is also included.


Assuntos
Alquinos/química , Níquel/química , Alcenos/síntese química , Catálise , Oxirredução , Propanóis/síntese química , Estereoisomerismo
7.
J Am Chem Soc ; 128(47): 15106-7, 2006 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-17117859

RESUMO

An enantioselective, convergent, total synthesis of (+)-acutiphycin (18 steps, longest linear sequence from commercial materials) features the first application of an alkynyl ether as a macrolactone precursor in total synthesis, as well as the first example of an intermolecular, SmI2-mediated, Reformatsky fragment coupling reaction. The high convergence, efficiency, and modular nature of this synthesis make it amenable to the synthesis of structurally related compounds.


Assuntos
Compostos Heterocíclicos/síntese química , Macrolídeos/síntese química , Antineoplásicos/síntese química , Cianobactérias/química , Estereoisomerismo
8.
Org Lett ; 8(3): 455-8, 2006 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-16435858

RESUMO

[reaction: see text]. A study of nickel-catalyzed reductive coupling reactions of aldehydes and chiral 1,6-enynes has provided evidence for three distinct mechanistic pathways that govern regioselectivity in this transformation. In the absence of a phosphine additive, high regioselectivity and high diastereoselectivity are obtained as a direct result of coordination of both the alkyne and the olefin to the metal center during the C-C bond-forming step.


Assuntos
Aldeídos/química , Alquinos/química , Níquel/química , Catálise , Estrutura Molecular , Oxirredução , Estereoisomerismo
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