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1.
Bioorg Med Chem Lett ; 22(3): 1421-6, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22226656

RESUMO

Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has been demonstrated that 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists show beneficial effect on cognition in several animal models. Based on a pharmacophore model reported in the literature, we have designed and successfully identified a 7-benzenesulfonyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine (3a) scaffold as a novel class of 5-HT(6) receptor antagonists. Despite good activity against 5-HT(6) receptor, 3a exhibited poor liver microsome stability in mouse, rat and dog. It was demonstrated that the saturation of the double bond of the tetrahydropyridine ring of 3a enhanced metabolic stability. However the resulting compound, 4a (7-phenylsulfonyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c] pyridine-HCl salt) exhibited ∼30-fold loss in potency along with introduction of two chiral centers. In our optimization process for this series, we found that substituents at the 2 or 3 positions on the distal aryl group are important for enhancing activity against 5-HT(6). Separation of enantiomers and subsequent optimization and SAR with bis substituted phenyl sulfone provided potent 5-HT(6) antagonists with improved PK profiles in rat. A potent, selective 5-HT(6)R antagonist (15k) was identified from this study which showed good oral bioavailability (F=39%) in rat with brain penetration (B/P=2.76) and in vivo activity in a rat social recognition test.


Assuntos
Encéfalo/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Sulfonas/química , Sulfonas/farmacologia , Animais , Cães , Humanos , Concentração Inibidora 50 , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Ratos , Receptores de Serotonina , Antagonistas da Serotonina/farmacocinética , Estereoisomerismo
2.
J Med Chem ; 55(1): 115-25, 2012 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-22141319

RESUMO

Chemical strategies to mitigate cytochrome P450-mediated bioactivation of novel 2,7-disubstituted pyrrolo[2,1-f][1,2,4]triazine ALK inhibitors are described along with synthesis and biological activity. Piperidine-derived analogues showing minimal microsomal reactive metabolite formation were discovered. Potent, selective, and metabolically stable ALK inhibitors from this class were identified, and an orally bioavailable compound (32) with antitumor efficacy in ALK-driven xenografts in mouse models was extensively characterized.


Assuntos
Compostos de Anilina/síntese química , Antineoplásicos/síntese química , Pirróis/síntese química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Triazinas/síntese química , Administração Oral , Quinase do Linfoma Anaplásico , Compostos de Anilina/farmacocinética , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Técnicas In Vitro , Camundongos , Camundongos SCID , Microssomos Hepáticos/metabolismo , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Triazinas/farmacocinética , Triazinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Bioorg Med Chem Lett ; 21(24): 7261-4, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-22061645

RESUMO

Anaplastic lymphoma kinase (ALK) is transmembrane receptor tyrosine kinase, with oncogenic variants that have been implicated in ALCL, NSCLC and other cancers. Screening of a VEGFR2-biased kinase library resulted in identification of 1 which showed cross-reactivity with ALK. SAR on the indole segment of 1 showed that a subtle structural modification (the ethoxy group of 1 changed to a benzyloxy to generate 5a) enhanced potency (ALK), selectivity for VEGFR2 and IR along with improvement in metabolic stability. From docking studies of ALK versus VEGFR2 kinase, we postulated that the loss of entropy of the VEGFR2 in the bound form with 5a might be the origin of the reduced activity against that protein. Modification of the heterocyclic segment showed that thiazole-bearing pyrazolones preserved enzyme potency, and enhanced inhibition of NPM-ALK autophosphorylation in ALK-positive ALCL cells (Karpas-299). SAR of the benzyloxy group resulted in compounds which demonstrated good cellular potency in Karpas-299 cells. Compound 8 showed best overall profile for the series with broad kinome selectivity and liver micorsome stability. Compound 8 showed reasonable iv PK in rat, but with little oral exposure.


Assuntos
Inibidores de Proteínas Quinases/química , Pirazolonas/química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Administração Oral , Quinase do Linfoma Anaplásico , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Simulação por Computador , Ativação Enzimática/efeitos dos fármacos , Indóis/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Pirazolonas/síntese química , Pirazolonas/farmacocinética , Pirazolonas/farmacologia , Ratos , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
4.
Bioorg Med Chem Lett ; 21(1): 164-7, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21123062

RESUMO

The HGF-c-Met signaling axis is an important paracrine mediator of epithelial-mesenchymal cell interactions involving the regulation of multiple cellular activities including cell motility, mitogenesis, morphogenesis, and angiogenesis. Dysregulation of c-Met signaling (e.g., overexpression or increased activation) is associated with the development of a wide range of tumor types; thus, inhibiting the HGF-c-Met pathway is predicted to lead to anti-tumor effects in many cancers. Elaboration of a 2-arylaminopyrimidine scaffold led to a series of potent c-Met inhibitors bearing a C4-2-amino-N-methylbenzamide group. Specifically, a series of C2-benzazepinone analogs demonstrated potent inhibition of c-Met in enzymatic and cellular assays. Kinase selectivity could be tuned by varying the nature of the alkyl group on the benzazepinone nitrogen.


Assuntos
Compostos Bicíclicos com Pontes/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirimidinas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Humanos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Relação Estrutura-Atividade
5.
ACS Med Chem Lett ; 1(9): 493-8, 2010 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-24900237

RESUMO

A series of novel 7-amino-1,3,4,5-tetrahydrobenzo[b]azepin-2-one derivatives within the diaminopyrimidine class of kinase inhibitors were identified that target anaplastic lymphoma kinase (ALK). These inhibitors are potent against ALK in an isolated enzyme assay and inhibit autophosphorylation of the oncogenic fusion protein NPM-ALK in anaplastic large cell lymphoma (ALCL) cell lines. The lead inhibitor 15, which incorporates a bicyclo[2.2.1]hept-5-ene ring system in place of an aryl moiety, activates the pro-apoptotic caspases (3 and 7) and displays selective cytotoxicity against ALK-positive ALCL cells. Furthermore, 15 provides more than 40-fold selectivity against the structurally related insulin receptor, is orally bioavailable in multiple species, and displays in vivo antitumor efficacy when dosed orally in ALK-positive ALCL tumor xenografts in Scid mice.

6.
Bioorg Med Chem Lett ; 18(12): 3551-5, 2008 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-18508265

RESUMO

An immobilized Staurosporine aglycone isostere where one of the indole nitrogen atoms was replaced by carbon has been sequentially functionalized to generate compounds inhibiting TrkA kinase. In the first phase, initial screening of a library of C13-hydroxymethyl-7-oxo-indenopyrrolocarbazoles resulted in several potent compounds, one of which was further optimized to generate the corresponding carbamates on solid phase. Some of the major carbamate diastereomers were found to be several-fold more potent than their alcohol parents. Synthesis, SAR analysis, kinase selectivity, and anti-tumor properties of a TrkA inhibitor (12a) are discussed.


Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirróis/química , Receptor trkA/antagonistas & inibidores , Estaurosporina/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Masculino , Conformação Molecular , Neoplasias Experimentais/tratamento farmacológico , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos , Ratos Sprague-Dawley , Bibliotecas de Moléculas Pequenas , Estaurosporina/análogos & derivados , Estereoisomerismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Bioorg Med Chem Lett ; 17(6): 1793-8, 2007 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-17239587

RESUMO

KDR kinase inhibition is considered to play an important role in regulating angiogenesis, which is vital for the survival and proliferation of tumor cells. Recently we disclosed a structure-based kinase inhibitor design strategy which led to the identification of a new class of VEGFR-2/KDR kinase inhibitors bearing heterocyclic substituted pyrazolones as the core template. Instability in a rat S9 preparation and poor iv PK profiles for most of these inhibitors necessitated exploration of new pyrazolones to identify new analogs with improved metabolic stability. Optimization of the heterocyclic moiety led to the identification of the thiadiazole series of pyrazolones (D) as potent VEGFR-2/KDR kinase inhibitors. SAR modifications, kinase selectivity profiling, and structural elements for improved PK properties were explored. Oral bioavailability up to 29% was achieved in the rat. Modeling results based on the Glide XP docking approach supported our postulation regarding the interaction of the lactam segment of the pyrazolones with the hinge region of the KDR kinase.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pirazolonas/síntese química , Pirazolonas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Autorradiografia , Disponibilidade Biológica , Western Blotting , Desenho de Fármacos , Inibidores Enzimáticos/farmacocinética , Humanos , Técnicas In Vitro , Modelos Moleculares , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Pirazolonas/farmacocinética , Ratos , Proteínas Recombinantes , Espectrometria de Fluorescência , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 16(8): 2158-62, 2006 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-16460933

RESUMO

Structural analysis of the essential binding elements of the oxindole-based kinase inhibitor (1) led to the identification of a novel class of heterocyclic-substituted pyrazolones. Knoevenagel condensation of a variety of activated methylene nucleophiles with indole or pyrrole carboxaldehydes provided a focused library of molecules, each containing elements of kinase pharmacophore probe. Initial screening for VEGFR-2 kinase inhibition eliminated several of the probes. Identification of an active pyrazolone motif and further optimization resulted in several highly potent VEGFR-2 inhibitors with cellular efficacy, anti-angiogenic activity ex vivo in rat aortic ring explant cultures, and oral anti-tumor efficacy in nude mice.


Assuntos
Antineoplásicos/síntese química , Inibidores Enzimáticos/síntese química , Pirazolonas/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/farmacologia , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Camundongos , Camundongos Nus , Pirazolonas/farmacologia , Ratos
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