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1.
J Med Chem ; 60(12): 4932-4948, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28537398

RESUMO

BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme (IC50 3.0 nM) with >10000-fold selectivity over human 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11ß-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Azetidinas/farmacologia , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Actinas/antagonistas & inibidores , Adamantano/administração & dosagem , Adamantano/química , Adamantano/farmacologia , Administração Oral , Animais , Azetidinas/administração & dosagem , Azetidinas/química , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Feminino , Meia-Vida , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Concentração Inibidora 50 , Macaca fascicularis , Masculino , Camundongos Obesos , Ratos , Relação Estrutura-Atividade
2.
Bioconjug Chem ; 27(5): 1276-84, 2016 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-27098672

RESUMO

A disulfide-bridged peptide drug development candidate contained two oligopeptide chains with 11 and 12 natural amino acids joined by a disulfide bond at the N-terminal end. An efficient biotechnology based process for the production of the disulfide-bridged peptide was developed. Initially, the two individual oligopeptide chains were prepared separately by designing different fusion proteins and expressing them in recombinant E. coli. Enzymatic or chemical cleavage of the two fusion proteins provided the two individual oligopeptide chains which could be conjugated via disulfide bond by conventional chemical reaction to the disulfide-bridged peptide. A novel heterodimeric system to bring the two oligopeptide chains closer and induce disulfide bond formation was designed by taking advantage of the self-assembly of a leucine zipper system. The heterodimeric approach involved designing fusion proteins with the acidic and basic components of the leucine zipper, additional amino acids to optimize interaction between the individual chains, specific cleavage sites, specific tag to ensure separation, and two individual oligopeptide chains. Computer modeling was used to identify the nature and number of amino acid residue to be inserted between the leucine zipper and oligopeptides for optimum interaction. Cloning and expression in rec E. coli, fermentation, followed by cell disruption resulted in the formation of heterodimeric protein with the interchain disulfide bond. Separation of the desired heterodimeric protein, followed by specific cleavage at methionine by cyanogen bromide provided the disulfide-bridged peptide.


Assuntos
Biotecnologia , Dissulfetos/química , Peptídeos/química , Peptídeos/metabolismo , Sequência de Aminoácidos , Escherichia coli/genética , Modelos Moleculares , Peptídeos/genética , Multimerização Proteica , Estrutura Quaternária de Proteína
3.
Org Lett ; 14(18): 4938-41, 2012 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-22954228

RESUMO

An enantioselective synthesis of the CGRP antagonist BMS-846372, amenable to large scale preparation, is presented. This new synthesis showcases a chemo- and enantioselective reduction of a cyclohepta[b]pyridine-5,9-dione as well as a Pd-catalyzed alpha-arylation reaction to form the key carbon-carbon bond and set the absolute and relative stereochemistry.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Catálise , Compostos Heterocíclicos de 4 ou mais Anéis/química , Estrutura Molecular , Estereoisomerismo
4.
Biotechnol Appl Biochem ; 53(Pt 2): 133-7, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18699775

RESUMO

A total of 39 microbes were screened for the ability to selectively N-demethylate (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1H-1,2,4-triazol-5-yl)aminopyrimidin-5-yl)-3,5-dihydroxy-hept-6-enoic acid (I), a potential drug for lowering blood cholesterol levels. Two Streptomyces species were found to carry out the desired N-demethylation. Bioconversion by Streptomyces griseus A.T.C.C. 13273 and product recovery were scaled up to the multi-gram level.


Assuntos
Bactérias/metabolismo , Fungos/metabolismo , Pirimidinas/metabolismo , Triazóis/metabolismo , Biotransformação , Metilação , Streptomyces/metabolismo
5.
Biotechnol Appl Biochem ; 45(Pt 2): 81-5, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16722823

RESUMO

Second-generation paclitaxel analogues that require replacement of the C-4 acetate by other substituents are in development. An enzyme able to specifically remove the C-4 acetate from paclitaxel could simplify preparation of the analogues. Several strains were isolated from soil samples that contain enzyme activities able to 4-deacetylate 10-DAB (10-deacetylbaccatin III). Selection was made using plates containing 10-DAB as the sole carbon source and screening colonies for deacetylation of 10-DAB. Two strains initially isolated were identified as Rhodococcus sp. and deposited with the A.T.C.C. (Manassas, VA, U.S.A.) as strains 202191 and 202192. Whole cells were able to convert 10-DAB into 4,10-DDAB (4-deacetyl-10-deacetylbaccatin III) in 90% yield. The enzyme activity in these strains was not effective with paclitaxel and 10-deacetylpaclitaxel, although 4,10-DDAB was produced from baccatin III. The activity in these strains was associated with an insoluble fraction of cell extracts. Several additional isolates were obtained that were identified as variants of Stenotrophomonas maltophilia, and a soluble C-4 deacetylase was purified approx. 218-fold from one of them. The activity of this enzyme was limited to 10-DAB, and the enzyme was not effective with paclitaxel or baccatin III.


Assuntos
Rhodococcus/enzimologia , Microbiologia do Solo , Taxoides/metabolismo , Acetilação , Alcaloides/metabolismo , Alcaloides/farmacologia , Aminoidrolases/isolamento & purificação , Antineoplásicos Fitogênicos/metabolismo , Proteínas de Bactérias/isolamento & purificação , Paclitaxel/metabolismo , Rhodococcus/isolamento & purificação , Stenotrophomonas maltophilia/enzimologia , Stenotrophomonas maltophilia/isolamento & purificação , Taxoides/farmacologia
7.
Biotechnol Appl Biochem ; 39(Pt 2): 209-14, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15032741

RESUMO

6-alpha-Hydroxy-7-deoxy-10-deacetylbaccatin-III is an intermediate that is potentially useful for synthesis of analogues of paclitaxel. Screening of microbial strains identified an enzyme activity in Nocardioides luteus SC 13912 (A.T.C.C. 55426) which converted 7-deoxy-10-deacetylbaccatin-III into 6-hydroxy-7-deoxy-10-deacetylbaccatin-III with a maximum yield of 44%.


Assuntos
Reatores Biológicos/microbiologia , Nocardia/classificação , Nocardia/metabolismo , Taxoides/isolamento & purificação , Taxoides/metabolismo , Antineoplásicos/isolamento & purificação , Antineoplásicos/metabolismo , Biotransformação , Hidrólise , Nocardia/crescimento & desenvolvimento , Projetos Piloto , Especificidade da Espécie
8.
Bioorg Med Chem Lett ; 13(10): 1751-3, 2003 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-12729657

RESUMO

A C-8 keto pleuromutilin derivative has been synthesized from the biotransformation product 8-hydroxy mutilin. A key step in the process was the selective oxidation at C-8 of 8-hydroxy mutilin using tetrapropylammonium perruthenate. The presence of the C-8 keto group precipitated interesting intramolecular chemistry to afford a compound (10) with a novel pleuromutilin-derived ring system.


Assuntos
Diterpenos/síntese química , Biotransformação , Cetonas/química , Oxirredução , Compostos Policíclicos/química
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