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1.
J Org Chem ; 74(10): 3933-5, 2009 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-19374382

RESUMEN

Photolysis of 1-(3-alkynoxy)-9,10-anthraquinones in deoxygenated methanol leads to moderate yields (35-45%) of 3-alkynals along with the unexpected formation of diacetals. Reaction of these 3-alkynals with Grignard and Wittig reagents occurs nearly quantitatively without rearrangement to their 2,3-dienal isomers.

2.
ACS Med Chem Lett ; 6(2): 156-61, 2015 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-25699143

RESUMEN

Several polar heteroaromatic acetic acids and their piperidine amides were synthesized and evaluated as ghrelin or type 1a growth hormone secretagogue receptor (GHS-R1a) inverse agonists. Efforts to improve pharmacokinetic and safety profile was achieved by modulating physicochemical properties and, more specifically, emphasizing increased polarity of our chemical series. ortho-Carboxamide containing compounds provided optimal physicochemical, pharmacologic, and safety profile. pH-dependent chemical stability was also assessed with our series.

3.
J Med Chem ; 57(10): 4273-88, 2014 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-24738581

RESUMEN

A novel series of nonsteroidal mineralocorticoid receptor (MR) antagonists identified as part of our strategy to follow up on the clinical candidate PF-03882845 (2) is reported. Optimization departed from the previously described pyrazoline 3a and focused on improving the selectivity for MR versus the progesterone receptor (PR) as an approach to avoid potential sex-hormone-related adverse effects and improving biopharmaceutical properties. From this effort, (R)-14c was identified as a potent nonsteroidal MR antagonist (IC50 = 4.5 nM) with higher than 500-fold selectivity versus PR and other related nuclear hormone receptors, with improved solubility as compared to 2 and pharmacokinetic properties suitable for oral administration. (R)-14c was evaluated in vivo using the increase of urinary Na(+)/K(+) ratio in rat as a mechanism biomarker of MR antagonism. Treatment with (R)-14c by oral administration resulted in significant increases in urinary Na(+)/K(+) ratio and demonstrated this novel compound acts as an MR antagonist.


Asunto(s)
Antagonistas de Receptores de Mineralocorticoides/síntesis química , Ácidos Nicotínicos/síntesis química , Pirazoles/síntesis química , Animales , Descubrimiento de Drogas , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacología , Simulación del Acoplamiento Molecular , Ácidos Nicotínicos/farmacología , Potasio/orina , Pirazoles/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Mineralocorticoides/química , Sodio/orina , Relación Estructura-Actividad
4.
ACS Med Chem Lett ; 5(5): 474-9, 2014 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-24900864

RESUMEN

The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing off-target pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials.

5.
Org Lett ; 11(14): 3140-2, 2009 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-19527001

RESUMEN

A novel method for the kinetic resolution of unsymmetrical acyclic allylic carbonates and the concurrent synthesis of enantioenriched secondary amines using a commercially available chiral catalyst is disclosed.


Asunto(s)
Compuestos Alílicos/química , Aminas/síntesis química , Carbonatos/química , Rodio/química , Aminas/química , Catálisis , Estructura Molecular , Estereoisomerismo
6.
Bioorg Med Chem Lett ; 17(20): 5693-7, 2007 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-17766112

RESUMEN

A series of amino-pyridines were synthesized and evaluated for androgen antagonist activities. Among these compounds, (R)-(+)-6-[methyl-(1-phenyl-ethyl)-amino]-4-trifluoromethyl-nicotinonitrile was the most active example of this class. This compound displayed potent androgen receptor antagonist activity as well as favorable pharmacokinetic characteristics for a potential topical agent. It also demonstrated remarkable potency for stimulating hair growth in a male C3H mouse model as well as reducing sebum production in the male Syrian hamster ear model.


Asunto(s)
Aminopiridinas/química , Aminopiridinas/farmacología , Antagonistas de Receptores Androgénicos , Cabello/efectos de los fármacos , Cabello/crecimiento & desarrollo , Sebo/efectos de los fármacos , Sebo/metabolismo , Aminopiridinas/síntesis química , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C3H , Modelos Moleculares , Estructura Molecular , Receptores Androgénicos/metabolismo , Relación Estructura-Actividad
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