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1.
Bioorg Med Chem Lett ; 74: 128929, 2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-35961461

RESUMO

Based on the structure of an early lead identified in Deciphera's proprietary compound collection of switch control kinase inhibitors and using a combination of medicinal chemistry guided structure activity relationships and structure-based drug design, a novel series of potent acyl urea-based CSF1R inhibitors was identified displaying high selectivity for CSF1R versus the other members of the Type III receptor tyrosine kinase (RTK) family members (KIT, PDGFR-α, PDGFR-ß, and FLT3), VEGFR2 and MET. Based on in vitro biology, in vitro ADME and in vivo PK/PD studies, compound 10 was selected as an advanced lead for Deciphera's CSF1R research program.


Assuntos
Receptores Proteína Tirosina Quinases , Ureia , Desenho de Fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas , Relação Estrutura-Atividade , Ureia/química , Ureia/farmacologia
2.
ACS Comb Sci ; 18(7): 387-93, 2016 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-27300570

RESUMO

Applications of silica-ROMP reagents in a one-pot, sequential protocol have been developed for the synthesis of a variety of diverse benzoxathiazepine 1,1-dioxides. This protocol includes sulfonylation, intramolecular SNAr, alkylation with silica-supported oligomeric benzyl (Si-OBPn) and triazole (Si-OTPn) phosphates, and intermolecular SNAr addition with a number of secondary amines in one-pot to afford a variety of unique benzoxathiazepine 1,1-dioxides sultams in good to excellent yields.


Assuntos
Alquilantes/química , Dióxido de Silício/química , Tiazepinas/síntese química , Alquilação , Aminas/síntese química , Aminas/química , Compostos de Benzil/síntese química , Indicadores e Reagentes , Óxidos , Fosfatos/química , Estereoisomerismo , Triazóis/síntese química
3.
J Org Chem ; 80(20): 9926-41, 2015 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-26446396

RESUMO

The generation of common and stereochemically rich medium-sized benzo-fused sultams via complementary pairing of heretofore-unknown (o-fluoroaryl)sulfonyl aziridine building blocks with an array of amino alcohols/amines in a modular one-pot, sequential protocol using an aziridine ring opening and intramolecular nucleophilic aromatic substitution is reported. The strategy employs a variety of amino alcohols/amines and proceeds with 6 + 4/6 + 5 and 6 + 1 cycloetherification pathways in a highly chemo- and regioselective fashion to obtain skeletally and structurally diverse, polycyclic, 10- to 11- and 7-membered benzo-fused sultams for broad-scale screening.


Assuntos
Aziridinas/química , Naftalenossulfonatos/síntese química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Naftalenossulfonatos/química
4.
Mol Cancer Ther ; 14(9): 2023-34, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26285778

RESUMO

Altiratinib (DCC-2701) was designed based on the rationale of engineering a single therapeutic agent able to address multiple hallmarks of cancer (1). Specifically, altiratinib inhibits not only mechanisms of tumor initiation and progression, but also drug resistance mechanisms in the tumor and microenvironment through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 (KDR) kinases. This profile was achieved by optimizing binding into the switch control pocket of all three kinases, inducing type II inactive conformations. Altiratinib durably inhibits MET, both wild-type and mutated forms, in vitro and in vivo. Through its balanced inhibitory potency versus MET, TIE2, and VEGFR2, altiratinib provides an agent that inhibits three major evasive (re)vascularization and resistance pathways (HGF, ANG, and VEGF) and blocks tumor invasion and metastasis. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood-brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases.


Assuntos
Aminopiridinas/farmacologia , Anilidas/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neovascularização Patológica , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Receptor TIE-2/antagonistas & inibidores , Microambiente Tumoral , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Aminopiridinas/química , Anilidas/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Bevacizumab/química , Bevacizumab/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Desenho de Fármacos , Quimioterapia Combinada , Feminino , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Concentração Inibidora 50 , Melanoma Experimental , Camundongos , Modelos Moleculares , Conformação Molecular , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas c-met/química , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor TIE-2/metabolismo , Proteínas Recombinantes , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Org Lett ; 16(1): 82-5, 2014 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-24313225

RESUMO

A one-pot, sequential protocol is reported that involves complementary ambiphile pairing (CAP) of a vinyl sulfonamide with a variety of unprotected amino acids via aza-Michael addition and subsequent intramolecular amidation. The method generates diverse, sp(3)-rich mono- and bicyclic acyl sultams in a highly scalable manner. Modular pairing of stereochemically rich building blocks allows quick access to all possible isomers. Extension to include one-pot, sequential 3-, 4-, and 5-multicomponent protocols is also discussed.


Assuntos
Compostos Bicíclicos com Pontes/síntese química , Sulfonamidas/síntese química , Compostos Bicíclicos com Pontes/química , Estrutura Molecular , Estereoisomerismo , Sulfonamidas/química
6.
Beilstein J Org Chem ; 8: 1293-302, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23019462

RESUMO

The efficient synthesis of an 80-member library of unique benzoxathiazocine 1,1-dioxides by a microwave-assisted, intermolecular nucleophilic aromatic substitution (S(N)Ar) diversification pathway is reported. Eight benzofused sultam cores were generated by means of a sulfonylation/S(N)Ar/Mitsunobu reaction pairing protocol, and subsequently diversified by intermolecular S(N)Ar with ten chiral, non-racemic amine/amino alcohol building blocks. Computational analyses were employed to explore and evaluate the chemical diversity of the library.

7.
ACS Comb Sci ; 14(4): 268-72, 2012 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-22384820

RESUMO

A combination of MACOS scale-out and ROMP-derived oligomeric triazole phosphates (OTP(n)) have been successfully utilized for the preparation of a 106-member library of triazole containing benzothiaoxazepine-1,1-dioxides. This report demonstrates the utilization of a suite of soluble OTP(n) reagents for facile (triazolyl)methylation of 10 MACOS-derived sultam scaffolds in purification-free process for parallel synthesis of small molecule collections for HTS.


Assuntos
Benzotiadiazinas/síntese química , Micro-Ondas , Óxidos/síntese química , Fosfatos/química , Bibliotecas de Moléculas Pequenas/síntese química , Triazóis/química , Benzotiadiazinas/química , Técnicas de Química Combinatória , Metilação , Estrutura Molecular , Óxidos/química , Bibliotecas de Moléculas Pequenas/química , Estereoisomerismo
8.
J Flow Chem ; 1(1): 32-39, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22116791

RESUMO

The generation of stereochemically-rich benzothiaoxazepine-1,1'-dioxides for enrichment of high-throughput screening collections is reported. Utilizing a microwave-assisted, continuous flow organic synthesis platform (MACOS), scale-out of core benzothiaoxazepine-1,1'-dioxide scaffolds has been achieved on multi-gram scale using an epoxide opening/S(N)Ar cyclization protocol. Diversification of these sultam scaffolds was attained via a microwave-assisted intermolecular S(N)Ar reaction with a variety of amines. Overall, a facile, 2-step protocol generated a collection of benzothiaoxazepine-1,1'-dioxides possessing stereochemical complexity in rapid fashion, where all 8 stereoisomers were accessed from commercially available starting materials.

9.
Chem Commun (Camb) ; 47(46): 12524-6, 2011 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-22027744

RESUMO

The utilization of a monomer-on-monomer (MoM) intramolecular Mitsunobu cyclization reaction employing norbornenyl-tagged (Nb-tagged) reagents is reported for the synthesis of benzofused thiadiazepine-dioxides. Facile purification was achieved via ring-opening metathesis (ROM) polymerization initiated by one of three metathesis catalyst methods: (i) free metathesis catalyst, (ii) surface-initiated catalyst-armed silica, or (iii) surface-initiated catalyst-armed Co/C magnetic nanoparticles.


Assuntos
Benzeno/química , Técnicas de Química Sintética/métodos , Tiadiazinas/química , Tiadiazinas/síntese química , Ciclização , Nanopartículas/química
10.
ACS Comb Sci ; 13(6): 653-8, 2011 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-21902243

RESUMO

The development of a microwave-assisted, intermolecular S(N)Ar protocol for the synthesis of a 126-member benzothiaoxazepine-1,1-dioxide library is reported. Diversification of 12 benzothiaoxazepine-1,1-dioxides was achieved in rapid fashion utilizing a variety of 2° amines and amino alcohols to generate an 80-member library. A second 48-member library was subsequently generated via a two-step alkylation, intermolecular S(N)Ar diversification protocol.


Assuntos
Benzotiadiazinas/síntese química , Técnicas de Química Combinatória/métodos , Micro-Ondas , Oxazepinas/síntese química , Óxidos/síntese química , Alquilação , Amino Álcoois/química , Benzotiadiazinas/química , Modelos Químicos , Oxazepinas/química , Óxidos/química , Sulfonamidas/química
11.
Org Lett ; 13(19): 5148-51, 2011 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-21899284

RESUMO

A reaction pairing strategy centered on utilization of a reaction triad (sulfonylation, S(N)Ar addition and Mitsunobu alkylation) generating skeletally diverse, tricyclic and bicyclic benzofused sultams is reported. Pairing sulfonylation and S(N)Ar reactions yields bridged, tricyclic and bicyclic benzofused sultams. Application of the Mitsunobu reaction in a sulfonylation-Mitsunobu-S(N)Ar pairing allows access to benzthiazocine-1,1-dioxides, while a simple change in the order of pairing to sulfonylation-S(N)Ar-Mitsunobu affords structurally different, bridged tricyclic benzofused sultams.


Assuntos
Compostos Heterocíclicos/síntese química , Sulfonamidas/síntese química , Estrutura Molecular
12.
Org Lett ; 13(1): 8-10, 2011 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-21121636

RESUMO

A monomer-on-monomer (MoM) Mitsunobu reaction utilizing norbornenyl-tagged (Nb-tagged) reagents is reported, whereby purification was rapidly achieved by employing ring-opening metathesis polymerization, which was initiated by any of three methods utilizing Grubbs catalyst: (i) free catalyst in solution, (ii) surface-initiated catalyst-armed silica, or (iii) surface-initiated catalyst-armed Co/C magnetic nanoparticles.


Assuntos
Polímeros/síntese química , Magnetismo , Nanopartículas Metálicas/química
13.
J Comb Chem ; 12(6): 850-4, 2010 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-20879738

RESUMO

The construction of a library of benzothiaoxazepine-1,1'-dioxides utilizing a one-pot, S(N)Ar diversification-ODCT(50) scavenging protocol is reported. This protocol combines microwave irradiation to facilitate the reaction, in conjunction with a soluble ROMP-derived scavenger (ODCT) to afford the desired products in good overall purity. Utilizing this protocol, a 78-member library was successfully synthesized and submitted for biological evaluation.


Assuntos
Oxazepinas/química , Óxidos/química , Bibliotecas de Moléculas Pequenas , Tiazóis/química , Técnicas de Química Combinatória/métodos , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química
15.
Org Lett ; 12(13): 2904-7, 2010 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-20521800

RESUMO

The development of new ROMP-based oligomeric benzyl phosphates (OBP(n)) is reported for use as soluble, stable benzylating reagents. These oligomeric reagents are readily synthesized from commercially available materials and conveniently polymerized and purified in a one-pot process, affording bench-stable, pure white, free-flowing solids on multigram scale. Utilization in benzylation reactions with a variety of nucleophiles is reported.


Assuntos
Compostos de Benzil/síntese química , Fosfatos/química , Compostos de Benzil/química , Conformação Molecular , Estereoisomerismo
16.
Org Lett ; 12(10): 2182-5, 2010 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-20394415

RESUMO

A formal, one-pot [4 + 4] cyclization pathway for the generation of eight-membered sultams via in situ generation of an ortho-quinone methide (o-QM) is reported. The pairing of ambiphilic synthons in a complementary fashion is examined whereby o-fluorobenzenesulfonamides are merged with in situ generated o-QM in a formal [4 + 4] cyclization pathway to afford 5,2,1-dibenzooxathiazocine-2,2-dioxide scaffolds under microwave (mW) conditions. The method reported represents the first use of an o-QM in a formal hetero [4 + 4] cyclization.


Assuntos
Indolquinonas/síntese química , Cristalografia por Raios X , Ciclização , Indolquinonas/química , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo
17.
Org Lett ; 12(6): 1216-9, 2010 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-20178346

RESUMO

A formal [4+3] epoxide cascade protocol utilizing ambiphilic sulfonamides and a variety of epoxides (masked ambiphiles) has been developed for the generation of benzothiaoxazepine-1,1'-dioxides and oxathiazepine-1,1'-dioxides. This protocol combines an epoxide ring-opening with either an S(N)Ar or oxa-Michael cyclization pathway.


Assuntos
Compostos de Epóxi/química , Sulfonamidas/química , Tiazepinas/síntese química , Ciclização , Estrutura Molecular , Estereoisomerismo , Tiazepinas/química
18.
Tetrahedron ; 65(16): 3180-3188, 2009 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-20161276

RESUMO

The development of new methods to skeletally diverse sultams based on a central α-halo benzene sulfonamide building block is reported. Several salient features of this building block are utilized in multiple reaction pathways, including the Heck reaction, C- and O-arylation, Sonogashira-Pauson-Khand, Sonogashira-intramolecular hydroamination, lithiative cyclization and domino aza-Michael Heck for the generation of 5-, 6- and 7-membered benzofused bicyclic and tricyclic sultams.

19.
Tetrahedron Lett ; 49(29-30): 4553-4555, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-19319202

RESUMO

A new high-load, oligomeric monoamine hydrochloride (OMAm*HCl) derived from ring-opening metathesis polymerization (ROMP) of norbornene methylamine is reported. This oligomeric amine has been shown to be an effective scavenger of acid chlorides, sulfonyl chlorides and isocyanates. The reagent can be synthesized in a straightforward protocol from the Diels-Alder reaction of dicyclopentadiene (DCPD) 1 with allylamine (neat), formation of the corresponding ammonium salt and subsequent ROM polymerization to afford the desired oligomeric ammonium salts.

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