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1.
J Med Chem ; 39(23): 4592-601, 1996 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-8917648

RESUMEN

A subset of antiandrogen compounds, the N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides 1, were found to activate ATP sensitive potassium channels (KATP) and represent a new class of potassium channel openers (PCOs). A structure-activity relationship was carried out on the western region of this series with the goal of obtaining an activator of the ATP sensitive potassium channel suitable for use in the treatment of urge urinary incontinence. In particular three large 4-(N-aryl) substituents, the (N-phenyl-N-methylamino)sulfonyl, benzoyl, and 4-pyridylsulfonyl moieties, yielded non-antiandrogen, KATP potassium channel openers (39, 41, and 64, respectively) that are bladder selective in an in vivo rat model that simultaneously measures bladder contractions, heart rate, and blood pressure. Substitutions of the aryl rings of 41 and 64 gave several derivatives that also display selectivity in the in vivo rat model; however, none appear to offer a substantial advantage over 41 and 64. The PCO activity of 41 and 64 resides in the (S)-(-) enantiomers. ZD6169, 41(S), has been selected into development for the treatment of urge urinary incontinence.


Asunto(s)
Amidas/química , Canales de Potasio/agonistas , Amidas/farmacología , Amidas/uso terapéutico , Animales , Cricetinae , Técnicas In Vitro , Contracción Muscular , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Ratas , Relación Estructura-Actividad , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/fisiología , Incontinencia Urinaria/tratamiento farmacológico
2.
Proteins ; 17(2): 193-202, 1993 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-8265566

RESUMEN

A novel analytical method for comparing molecular shapes by optimizing the intersection of molecular "SKINS" has been developed. This method provides a quantitative measure of the shape similarity by maximizing the intersection volume of molecular surfaces with a finite thickness; a molecular skin. We report shape matching of a small tripeptide inhibitor (DFKi) of elastase class proteins with the 56 residue turkey ovomucoid inhibitor (TOMI). To match a large elastase inhibitor such as TOMI with a small inhibitor or drug, we found that it is necessary to use a skin match rather than molecular volume. Skin based comparisons of TOMI protein with DFKi successfully found the alignment expected from comparison of their respective crystallographic complexes with elastase (i.e. HLE/TOMI complex and PPE/tripeptide complex). In the skin comparison of the tripeptide with the TOMI protein, blind searching for skin matches involved optimization of the skin intersection from 172 starting positions randomly selected from a set of 500 points on the TOMI van der Waals surface [within 9.5 A of the Leu-18 on the TOMI binding loop (1 point/A2)]. The tripeptide center of mass was placed at these points and its orientation was randomized before optimization was initiated. The best skin intersection, 86.4 A3, was found three times and corresponds to the experimental alignment. The next best skin intersection was 78.1 A3 giving a discrimination factor in this case of 10%. Searches over the entire surface of the TOMI protein did not identify any new matches with skin intersection greater than 78.1 A3. Matching the DFKi with a TOMI structure relaxed from its crystal conformation by molecular dynamics gives similar results.


Asunto(s)
Oligopéptidos/química , Conformación Proteica , Inhibidor de Tripsina Pancreática de Kazal/química , Secuencia de Aminoácidos , Sustancias Macromoleculares , Modelos Químicos , Modelos Moleculares , Datos de Secuencia Molecular , Ovomucina/antagonistas & inhibidores , Elastasa Pancreática/antagonistas & inhibidores , Propiedades de Superficie
3.
J Med Chem ; 36(9): 1230-8, 1993 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-8487259

RESUMEN

A new and powerful analytical method for comparing molecular shapes by optimizing the overlap of molecular volumes has been developed. This shape comparison method provides both a quantitative measure of the shape similarity of molecules and a means to align molecules such that shape similarity if maximized. Our MSC method has been enhanced with an option to allow discrimination between groups with different chemical properties. Atoms or groups of atoms may be assigned to different classes based on specific properties such as electrostatic potential, hydrogen bonding ability, or hydrophobicity. This enables matches based on criteria such as alignment of hydrophobic groups or hydrogen bond acceptor groups. In this study, we report shape comparisons of angiotensin II (AII) receptor antagonists from two structural classes, 4-(biphenyl-4-ylmethoxy)-quinoline derivatives such as ICI D8731 and N-(biphenyl-4-ylmethyl)imidazole derivatives, such as DuP753. Starting with a list of low-energy conformations for the two molecules, each conformation of the first molecule is paired with each of the conformations of the second molecule. For each of these conformational pairs, an MSC comparison, which generates multiple MSC maxima, is initiated. Eight high scoring conformational pairings were found with shape matching based on the intersection of the total molecular volume, while nine high-scoring pairs were identified with matching by atom type. MSC identifies conformational pairs with high shape similarity, as measured by the intersection volume, and thus generates and prioritizes several alternative models for the AII antagonist pharmacophore.


Asunto(s)
Antagonistas de Receptores de Angiotensina , Compuestos de Bifenilo/química , Imidazoles/química , Quinolinas/química , Tetrazoles/química , Fenómenos Químicos , Química Física , Simulación por Computador , Electroquímica , Enlace de Hidrógeno , Losartán , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Programas Informáticos
4.
J Med Chem ; 35(22): 4027-38, 1992 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-1433210

RESUMEN

A novel series of nonpeptidic angiotensin II (AII) receptor antagonists is reported, derived from linkage of the biphenylcarboxylic acid or biphenylyltetrazole moiety found in previously described antagonists via a methyleneoxy chain to the 4-position of a 2-alkyl quinoline. When evaluated in an in vitro binding assay using a guinea pig adrenal membrane preparation, compounds in this series generally gave IC50 values in the range 0.01-1 microM. Structure-activity studies showed the quinoline nitrogen atom and a short alkyl chain at the quinoline 2-position to be essential for receptor binding. On intravenous administration in a normotensive rat model, the more potent compounds inhibited the AII-induced pressor response with ED50 values in the range 0.1-2.0 mg/kg. One of the compounds, 2-ethyl-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methoxy]quinoline (5g), demonstrated good oral activity in two rat models. At doses in the range 1-10 mg/kg in AII-infused, normotensive rats, the compound exhibited a dose-related inhibition of the pressor response with a good duration of action at the higher doses. In a renal hypertensive rat model, compound 5g showed a rapid and sustained lowering of blood pressure at a dose of 5 mg/kg. On the basis of its profile, this compound, designated ICI D8731, has been selected for clinical evaluation.


Asunto(s)
Antagonistas de Receptores de Angiotensina , Antihipertensivos/síntesis química , Quinolinas/síntesis química , Angiotensina II/antagonistas & inhibidores , Animales , Antihipertensivos/química , Antihipertensivos/farmacología , Unión Competitiva , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Cobayas , Enlace de Hidrógeno , Hipertensión Renal/fisiopatología , Técnicas In Vitro , Masculino , Modelos Moleculares , Conformación Molecular , Quinolinas/química , Quinolinas/metabolismo , Quinolinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Receptores de Angiotensina/metabolismo , Relación Estructura-Actividad , Difracción de Rayos X
5.
J Med Chem ; 35(5): 877-85, 1992 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-1548677

RESUMEN

On the basis of an extension of the literature lead 1, a series of benzimidazoles have been synthesized and shown to be angiotensin II (AII) receptor antagonists. The structure-activity relationships of these new antagonists have been explored and the key binding interactions defined. Molecular mechanics calculations were carried out on analogues of imidazole AII antagonists and conformationally restricted analogues were synthesized. The benzimidazole antagonists displaced AII in binding studies in vitro with IC50 values in the range 10(-5)-10(-7) M and antagonized the hypertensive effects of AII in vivo (rats) following intravenous administration with ED50 values in the range of 5-20 mg/kg.


Asunto(s)
Antagonistas de Receptores de Angiotensina , Bencimidazoles/síntesis química , Angiotensina II/antagonistas & inhibidores , Angiotensina II/metabolismo , Angiotensina II/farmacología , Animales , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Unión Competitiva , Presión Sanguínea/efectos de los fármacos , Cobayas , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Masculino , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Conejos , Ratas , Ratas Endogámicas , Relación Estructura-Actividad
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