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1.
J Med Chem ; 63(15): 8534-8553, 2020 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-32706964

RESUMEN

Starting from RO6800020 (1), our former γ-secretase modulator (GSM) lead compound, we utilized sequential structural replacements to improve the potency (IC50), pharmacokinetic properties including the free fraction (fraction unbound (fu)) in plasma, and in vivo efficacy. Importantly, we used novel CF3-alkoxy groups as bioisosteric replacements of a fluorinated phenyl ring and properties such as lipophilicity, solubility, metabolic stability, and free fraction could be balanced, maintaining low Pgp efflux needed for CNS penetration. In addition, by reducing aromaticity, we prevented phototoxicity. Additional substitution in the triazolopyridine core disturbed the binding to phosphatidylinositol 4-kinase, catalytic ß (PIK4CB). We also introduced less lipophilic head heterocycles devoid of covalent binding (CVB) liability. After these changes, further modifications to the trifluoroethoxy bioisosteric replacement allowed rebalancing of properties, such as lipophilicity, and also potency. Our optimization strategy culminated with in vivo active RO7101556 (18B) having excellent properties and being selected as an advanced candidate.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Péptidos beta-Amiloides/metabolismo , Animales , Línea Celular , Inhibidores Enzimáticos/farmacocinética , Humanos , Ratones Transgénicos , Modelos Moleculares , Neuronas/efectos de los fármacos , Neuronas/metabolismo
2.
ACS Med Chem Lett ; 11(6): 1257-1268, 2020 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-32551009

RESUMEN

γ-Secretase (GS) is a key target for the potential treatment of Alzheimer's disease. While inhibiting GS led to serious side effects, its modulation holds a lot of potential to deliver a safe treatment. Herein, we report the discovery of a potent and selective gamma secretase modulator (GSM) (S)-3 (RO7185876), belonging to a novel chemical class, the triazolo-azepines. This compound demonstrates an excellent in vitro and in vivo DMPK profile. Furthermore, based on its in vivo efficacy in a pharmacodynamic mouse model and the outcome of the dose range finding (DRF) toxicological studies in two species, this compound was selected to undergo entry in human enabling studies (e.g., GLP toxicology and scale up activities).

3.
Bioorg Med Chem Lett ; 26(20): 5092-5097, 2016 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-27658368

RESUMEN

Dual inhibition of fatty acid binding proteins 4 and 5 (FABP4 and FABP5) is expected to provide beneficial effects on a number of metabolic parameters such as insulin sensitivity and blood glucose levels and should protect against atherosclerosis. Starting from a FABP4 selective focused screening hit, biostructure information was used to modulate the selectivity profile in the desired way and to design potent dual FABP4/5 inhibitors with good selectivity against FABP3. With very good pharmacokinetic properties and no major safety alerts, compound 12 was identified as a suitable tool compound for further in vivo investigations.


Asunto(s)
Proteínas de Unión a Ácidos Grasos/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Diseño de Fármacos , Proteínas de Unión a Ácidos Grasos/química , Ratones , Ratones Noqueados , Farmacocinética , Conformación Proteica , Homología de Secuencia de Aminoácido
4.
J Med Chem ; 59(9): 4087-102, 2016 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-26878596

RESUMEN

We present a series of small molecule drug discovery case studies where computational methods were prospectively employed to impact Roche research projects, with the aim of highlighting those methods that provide real added value. Our brief accounts encompass a broad range of methods and techniques applied to a variety of enzymes and receptors. Most of these are based on judicious application of knowledge about molecular conformations and interactions: filling of lipophilic pockets to gain affinity or selectivity, addition of polar substituents, scaffold hopping, transfer of SAR, conformation analysis, and molecular overlays. A case study of sequence-driven focused screening is presented to illustrate how appropriate preprocessing of information enables effective exploitation of prior knowledge. We conclude that qualitative statements enabling chemists to focus on promising regions of chemical space are often more impactful than quantitative prediction.


Asunto(s)
Diseño de Fármacos , Conformación Molecular , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad
5.
Chimia (Aarau) ; 69(7-8): 407-13, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26507592

RESUMEN

Medicinal chemistry has been transformed by major technological and conceptual innovations over the last three decades: structural biology and bioinformatics, structure and property based molecular design, the concepts of multidimensional optimization (MDO), in silico and experimental high-throughput molecular property analysis. The novel technologies advanced gradually and in synergy with biology and Roche has been at the forefront. Applications in drug discovery programs towards new medicines in cardiovascular and metabolic diseases are highlighted to show impact and advancement: the early discovery of endothelin antagonists for endothelial dysfunction (Bosentan), 11-beta hydroxysteroid dehydrogenase (11ß-HSD1) inhibitors for dysregulated cellular glucocorticoid tonus (type 2 diabetes and metabolic syndrome) and non-covalent hormone sensitive lipase (HSL) inhibitors to study the scope of direct inhibition of lipolysis in the conceptual frame of lipotoxicity and type 2 diabetes.


Asunto(s)
Enfermedades Cardiovasculares/tratamiento farmacológico , Química Farmacéutica/tendencias , Sistemas de Liberación de Medicamentos , Enfermedades Metabólicas/tratamiento farmacológico , Animales , Fármacos Cardiovasculares/uso terapéutico , Diseño de Fármacos , Humanos
6.
Chimia (Aarau) ; 69(7): 407-413, 2015 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-28482972

RESUMEN

Medicinal chemistry has been transformed by major technological and conceptual innovations over the last three decades: structural biology and bioinformatics, structure and property based molecular design, the concepts of multidimensional optimization (MDO), in silico and experimental high-throughput molecular property analysis. The novel technologies advanced gradually and in synergy with biology and Roche has been at the forefront. Applications in drug discovery programs towards new medicines in cardiovascular and metabolic diseases are highlighted to show impact and advancement: the early discovery of endothelin antagonists for endothelial dysfunction (Bosentan), 11-beta hydroxysteroid dehydrogenase (11ß-HSD1) inhibitors for dysregulated cellular glucocorticoid tonus (type 2 diabetes and metabolic syndrome) and non-covalent hormone sensitive lipase (HSL) inhibitors to study the scope of direct inhibition of lipolysis in the conceptual frame of lipotoxicity and type 2 diabetes.

7.
Chimia (Aarau) ; 64(9): 662-6, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-21138110

RESUMEN

During a half-day symposium, the topic 'Channels and Transporters' was covered with five lectures, including a presentation on 'Introduction and Basics of Channels and Transporters' by Beat Ernst, lectures on structure, function and physiology of channels and transporters ('The Structural Basis for Ion Conduction and Gating in Pentameric Ligand-Gated Ion Channels' by Raimund Dutzler and 'Uptake and Efflux Transporters for Endogenous Substances and for Drugs' by Dietrich Keppler), and a case study lecture on 'Avosentan' by Werner Neidhart. The program was completed by Matthias Hediger who introduced to the audience the National Center of Competence in Research (NCCR)-TransCure in his lecture entitled 'From Transport Physiology to Identification of Therapeutic Targets'.


Asunto(s)
Antineoplásicos/farmacología , Proteínas Portadoras/fisiología , Canales Iónicos/fisiología , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Congresos como Asunto , Humanos
8.
J Med Chem ; 51(7): 2115-27, 2008 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-18335976

RESUMEN

The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chemical tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB1R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compounds, showing in vivo activity. These compounds reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-weight gain, as well as fat mass, in diet-induced obese Sprague-Dawley rats. Herein, we disclose the tools and strategies that were employed for rapid hit identification, synthesis and generation of structure-activity relationships, ultimately leading to the identification of (+)-[( R)-2-(2,4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone ( R)-14g . Biochemical, pharmacokinetic, and pharmacodynamic characteristics of ( R)-14g are discussed.


Asunto(s)
Fármacos Antiobesidad/administración & dosificación , Fármacos Antiobesidad/farmacología , Benzodioxoles/administración & dosificación , Benzodioxoles/farmacología , Obesidad/tratamiento farmacológico , Receptor Cannabinoide CB1/agonistas , Animales , Fármacos Antiobesidad/química , Benzodioxoles/síntesis química , Benzodioxoles/química , Peso Corporal/efectos de los fármacos , Cristalografía por Rayos X , Ciclohexanoles/antagonistas & inhibidores , Ciclohexanoles/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Hipotermia/inducido químicamente , Ligandos , Masculino , Ratones , Microsomas/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/química , Relación Estructura-Actividad
10.
Bioorg Med Chem Lett ; 15(14): 3446-9, 2005 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-15951170

RESUMEN

Sets of isomeric thiazole derivatives 1 and 2 have been synthesised in a parallel iterative solution-phase synthesis approach guided by the SAR analysis derived from biological results and computer-aided design and analysis. This synergistic and streamlined working procedure led to highly active isomeric NPY5 receptor ligands. However, a 10-fold difference at least in their respective binding affinities was consistently found for all isomeric pairs 1 and 2. The analysis of conformational differences due to heteroatom interactions in 1 and 2 revealed a favourable C=O...S interaction in 1, whereas thiazoles 2 showed a repulsive C=O...N interaction.


Asunto(s)
Receptores de Neuropéptido Y/antagonistas & inhibidores , Tiazoles/farmacología , Diseño Asistido por Computadora , Cristalografía por Rayos X , Isomerismo , Ligandos , Modelos Moleculares , Conformación Molecular , Relación Estructura-Actividad , Tiazoles/síntesis química
11.
Neuropharmacology ; 48(7): 1043-55, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15857631

RESUMEN

The human Neuropeptide Y (NPY) receptors 1 (hY1), 2 (hY2), 4 (hY4), and the mouse type 5 (mY5) receptor were expressed in human embryonic kidney 293 (HEK293) cells. The receptors bound a radioiodinated NPY ligand with high affinity and various NPY analogs competed for binding in a receptor selective-manner. Similarly, cAMP-inhibition and GTPgammaS binding assays were established. The four NPY receptors were further tested in the fluorimetric imaging plate reader (FLIPR) format, a cellular high-throughput assay, in the absence and presence of chimeric G proteins, Gqo5, Gqi5 and Gqi9. The receptors stimulated transient calcium release only in the presence of chimeric G proteins. While hY1, hY2 and hY4 receptors coupled to Gqo5, Gqi5 and Gqi9, the mY5 receptor stimulated transient calcium release only when co-expressed with Gqi9. Using an in silico screening approach we identified a small molecule 3-(5-benzoyl-thiazol-2-ylamino)-benzonitrile (compound 1), which bound to the mY5 receptor with high affinity (Ki=32.1+/-1.8 nM), competitively antagonized NPY-mediated GTPgammaS binding and calcium stimulation with high potency, and had no affinity for other NPY receptors. These data show that NPY receptors can be functionally coupled to the FLIPR readout, allowing for high throughput compound testing and identification of novel molecules.


Asunto(s)
Neuropéptido Y/metabolismo , Nitrilos/farmacología , Receptores de Neuropéptido Y/antagonistas & inhibidores , Receptores de Neuropéptido Y/fisiología , Tiazoles/farmacología , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Neuropéptido Y/análogos & derivados , Neuropéptido Y/farmacología , Nitrilos/química , Nitrilos/metabolismo , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Tiazoles/química , Tiazoles/metabolismo
12.
Bioorg Med Chem Lett ; 15(6): 1599-603, 2005 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-15745805

RESUMEN

In the quest for NPY5 receptor antagonists a virtual screening approach yielded a novel and potent hit class from a limited compound selection. The tight and seamless integration between virtual screening and rapid parallel chemistry within the framework of the Roche Lead Generation unit led in only two rounds of iterative chemistry optimisation to a much broader understanding of the factors which influence the potency of the thiazole hit class.


Asunto(s)
Receptores de Neuropéptido Y/antagonistas & inhibidores , Receptores de Neuropéptido Y/química , Animales , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Diseño de Fármacos , Ratones , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Relación Estructura-Actividad
13.
J Med Chem ; 45(1): 137-42, 2002 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-11754585

RESUMEN

A computer-based method was developed for rapid and automatic identification of potential "frequent hitters". These compounds show up as hits in many different biological assays covering a wide range of targets. A scoring scheme was elaborated from substructure analysis, multivariate linear and nonlinear statistical methods applied to several sets of one and two-dimensional molecular descriptors. The final model is based on a three-layered neural network, yielding a predictive Matthews correlation coefficient of 0.81. This system was able to correctly classify 90% of the test set molecules in a 10-times cross-validation study. The method was applied to database filtering, yielding between 8% (compilation of trade drugs) and 35% (Available Chemicals Directory) potential frequent hitters. This filter will be a valuable tool for the prioritization of compounds from large databases, for compound purchase and biological testing, and for building new virtual libraries.


Asunto(s)
Bases de Datos Factuales , Compuestos Orgánicos/química , Modelos Lineales , Estructura Molecular , Redes Neurales de la Computación , Dinámicas no Lineales , Preparaciones Farmacéuticas/química
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