RESUMEN
Background: To prioritize compounds with a higher likelihood of success, artificial intelligence models can be used to predict absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of molecules quickly and efficiently. Methods: Models were trained with BioPrint database proprietary data along with public datasets to predict various ADMET end points for the SAFIRE platform. Results: SAFIRE models performed at or above 75% accuracy and 0.4 Matthew's correlation coefficient with validation sets. Training with both proprietary and public data improved model performance and expanded the chemical space on which the models were trained. The platform features scoring functionality to guide user decision-making. Conclusion: High-quality datasets along with chemical space considerations yielded ADMET models performing favorably with utility in the drug discovery process.
Asunto(s)
Inteligencia Artificial , Descubrimiento de Drogas , Bases de Datos FactualesRESUMEN
A series of potential new 5-HT2 receptor scaffolds based on a simplification of the clinically studied, 5-HT2CR agonist vabicaserin, were designed. An in vivo feeding assay early in our screening process played an instrumental part in the lead identification process, leading us to focus on a 6,5,7-tricyclic scaffold. A subsequent early SAR investigation provided potent agonists of the 5-HT2C receptor that were highly selective in both functional and binding assays, had good rat PK properties and that significantly reduced acute food intake in the rat.
Asunto(s)
Benzodiazepinas/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacología , Receptor de Serotonina 5-HT2C/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Animales , Benzodiazepinas/síntesis química , Benzodiazepinas/metabolismo , Benzodiazepinas/farmacocinética , Perros , Descubrimiento de Drogas , Estabilidad de Medicamentos , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/metabolismo , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Humanos , Macaca fascicularis , Masculino , Ratones , Microsomas/metabolismo , Estructura Molecular , Ratas Sprague-Dawley , Agonistas del Receptor de Serotonina 5-HT2/síntesis química , Agonistas del Receptor de Serotonina 5-HT2/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/farmacocinética , Relación Estructura-ActividadRESUMEN
The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of 5c (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family and a more modest 30- to 50-fold selectivity over the EP3 receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP receptor dependent cAMP accumulation assays. 5c had an excellent PK profile across species. Enterohepatic recirculation most probably contributes to a concentration-time profile after oral administration in the cynomolgus monkey that showed a very low peak-to-trough ratio. Following the identification of an acceptable solid form, 5c was selected for further development for the treatment of PAH.
Asunto(s)
Acetatos/uso terapéutico , Carbamatos/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Receptores de Prostaglandina/agonistas , Acetatos/farmacocinética , Administración Oral , Animales , Disponibilidad Biológica , Carbamatos/farmacocinética , Descubrimiento de Drogas , Ratas , Relación Estructura-ActividadRESUMEN
G-protein coupled receptor (GPCR) GPR109a is a molecular target for nicotinic acid and is expressed in adipocytes, spleen, and immune cells. Nicotinic acid has long been used for the treatment of dyslipidemia due to its capacity to positively affect serum lipids to a greater extent than other currently marketed drugs. We report a series of tricyclic pyrazole carboxylic acids that are potent and selective agonists of GPR109a. Compound R,R-19a (MK-1903) was advanced through preclinical studies, was well tolerated, and presented no apparent safety concerns. Compound R,R-19a was advanced into a phase 1 clinical trial and produced a robust decrease in plasma free fatty acids. On the basis of these results, R,R-19a was evaluated in a phase 2 study in humans. Because R,R-19a produced only a weak effect on serum lipids as compared with niacin, we conclude that the beneficial effects of niacin are most likely the result of an undefined GPR109a independent pathway.
Asunto(s)
Ácidos Grasos no Esterificados/sangre , Pirazoles/uso terapéutico , Receptores Acoplados a Proteínas G/agonistas , Animales , Humanos , Hipolipemiantes/farmacocinética , Hipolipemiantes/uso terapéutico , Masculino , Niacina/farmacología , Pirazoles/síntesis química , Pirazoles/farmacocinética , Ratas , Receptores Acoplados a Proteínas G/efectos de los fármacos , Receptores Nicotínicos/efectos de los fármacos , Estereoisomerismo , Vasodilatadores/farmacologíaRESUMEN
The design and synthesis of a second generation GPR119-agonist clinical candidate for the treatment of diabetes is described. Compound 16 (APD597, JNJ-38431055) was selected for preclinical development based on a good balance between agonist potency, intrinsic activity and in particular on its good solubility and reduced drug-drug interaction potential. In addition, extensive in vivo studies showed a more favorable metabolic profile that may avoid the generation of long lasting metabolites with the potential to accumulate in clinical studies.
Asunto(s)
Descubrimiento de Drogas , Hipoglucemiantes/química , Piperidinas/química , Piperidinas/farmacocinética , Piridinas/química , Piridinas/farmacocinética , Receptores Acoplados a Proteínas G/agonistas , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Modelos Animales de Enfermedad , Humanos , Hipoglucemiantes/farmacocinética , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Ratas , Ratas Sprague-DawleyRESUMEN
We herein outline the design of a new series of agonists of the pancreatic and GI-expressed orphan G-protein coupled receptor GPR119, a target that has been of significant recent interest in the field of metabolism, starting from our prototypical agonist AR231453. A number of key parameters were improved first by incorporation of a pyrazolopyrimidine core to create a new structural series and secondly by the introduction of a piperidine ether group capped with a carbamate. Chronic treatment with one compound from the series, 3k, showed for the first time that blood glucose and glycated hemoglobin (HbA1c) levels could be significantly reduced in Zucker Diabetic Fatty (ZDF) rats over several weeks of dosing. As a result of these and other data described here, 3k (APD668, JNJ-28630368) was the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes.
Asunto(s)
Glucemia/efectos de los fármacos , Descubrimiento de Drogas , Hipoglucemiantes/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Modelos Animales de Enfermedad , Glucosa/metabolismo , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Estructura Molecular , Oxadiazoles/química , Oxadiazoles/farmacología , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Ratas ZuckerRESUMEN
Tricyclic pyrazole tetrazoles which are potent partial agonists of the high affinity niacin receptor, GPR109a, have been discovered and optimized. One of these compounds has proven to be effective at lowering free fatty acids in vitro and in vivo.
Asunto(s)
Pirazoles/química , Receptores Acoplados a Proteínas G/agonistas , Tetrazoles/química , Vasodilatadores/química , Animales , Perros , Haplorrinos , Humanos , Ratones , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismo , Tetrazoles/síntesis química , Tetrazoles/farmacocinética , Vasodilatadores/síntesis química , Vasodilatadores/farmacocinéticaRESUMEN
A series of 5-N,N-disubstituted-5-aminopyrazole-3-carboxylic acids were prepared and found to act as highly potent and selective agonists of the G-Protein Coupled Receptor (GPCR) GPR109b, a low affinity receptor for niacin and some aromatic d-amino acids. Little activity was observed at the highly homologous higher affinity niacin receptor, GPR109a.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Receptores Acoplados a Proteínas G/agonistas , Animales , Aterosclerosis/tratamiento farmacológico , Células CHO , Ácidos Carboxílicos/farmacología , Química Farmacéutica/métodos , Cricetinae , Cricetulus , Diseño de Fármacos , Dislipidemias/tratamiento farmacológico , Humanos , Ligandos , Lipoproteínas HDL/química , Lipoproteínas LDL/química , Modelos Químicos , Niacina/química , Pirazoles/farmacología , Receptores Acoplados a Proteínas G/metabolismo , Receptores NicotínicosRESUMEN
Inferring the relative bioactive poses between active molecules is a common problem in drug discovery. The use of rapid pairwise alignment algorithms in conjunction with rigid conformer libraries has become a prevalent approach to this problem. These programs can be easily used to compare two molecules or suggest alternatives to a single known active. However, it is not obvious how to combine pairwise alignments between multiple actives into an overlay that reproduces the binding mode of those actives in the target receptor. We describe a new algorithm, DIFGAPE (DIstance geometry Focused Genetic Algorithm Pose Evaluator) that, given pairwise alignments of conformers of active compounds, attempts to reproduce overlays of ligand binding modes. The software was evaluated on 13 test systems from 9 protein targets using associated ligands extracted from the PDB. Starting from 2D ligand structures with no protein information, we were able in 4 systems to approximate the crystallographically observed binding mode. For example, the prediction for a set of 11 ligands targeting FXa had 1.6 A rmsd to crystal structure coordinates. Finally, the evaluation illustrated current challenges for molecular conformer generators and pairwise alignment algorithms.
Asunto(s)
Algoritmos , Descubrimiento de Drogas , Proteínas/metabolismo , Animales , Cristalografía por Rayos X , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Unión Proteica , Conformación Proteica , Proteínas/químicaRESUMEN
The discovery and profiling of 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (5a, MK-0354), a partial agonist of GPR109a, is described. Compound 5a retained the plasma free fatty acid lowering effects in mice associated with GPR109a agonism, but did not induce vasodilation at the maximum feasible dose. Moreover, preadministration of 5a blocked the flushing effect induced by nicotinic acid but not that induced by PGD2. This profile made 5a a suitable candidate for further study for the treatment of dyslipidemia.
Asunto(s)
Hipolipemiantes/farmacología , Pirazoles/farmacocinética , Receptores Acoplados a Proteínas G/agonistas , Tetrazoles/farmacocinética , Adipocitos/efectos de los fármacos , Animales , Ácidos Grasos no Esterificados/sangre , Humanos , Hipolipemiantes/síntesis química , Hipolipemiantes/uso terapéutico , Lipólisis/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Pirazoles/síntesis química , Receptores Nicotínicos , Tetrazoles/síntesis química , Vasodilatación/efectos de los fármacosRESUMEN
A series of 3-nitro-4-substituted-aminobenzoic acids were prepared and found to act as potent and highly selective agonists of the orphan human GPCR GPR109b, a low affinity receptor for niacin. No activity was observed at the closely homologous high affinity niacin receptor, GPR109a. A second series, comprising 6-amino-substituted nicotinic acids was, also prepared and several analogues showed comparable activity to the nitroaryl series.
Asunto(s)
Benzoatos/química , Ácidos Nicotínicos/química , Receptores Acoplados a Proteínas G/agonistas , Animales , Benzoatos/agonistas , Benzoatos/metabolismo , Células CHO , Cricetinae , Cricetulus , Humanos , Niacina/metabolismo , Ácidos Nicotínicos/agonistas , Ácidos Nicotínicos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/fisiología , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/fisiología , Relación Estructura-ActividadRESUMEN
A strategy for lead identification of new agonists of GPR109a, starting from known compounds shown to activate the receptor, is described. Early compound triage led to the formulation of a binding hypothesis and eventually to our focus on a series of pyrazole acid derivatives. Further elaboration of these compounds provided a series of 5,5-fused pyrazoles to be used as lead compounds for further optimization.
Asunto(s)
Ácidos Heterocíclicos/química , Química Farmacéutica/métodos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/química , Receptores Nicotínicos/química , Adipocitos/metabolismo , Animales , AMP Cíclico/metabolismo , Diseño de Fármacos , Humanos , Cinética , Modelos Químicos , Niacina/química , Pirazoles/química , Ratas , Bazo/metabolismoRESUMEN
Recently identified GPCRs, GPR109a and GPR109b, the high and low affinity receptors for niacin, may represent good targets for the development of HDL elevating drugs for the treatment of atherosclerosis. Acifran, an agonist of both receptors, has been tested in human subjects, yet until recently very few analogs had been reported. We describe a series of acifran analogs prepared using newly developed synthetic pathways and evaluated as agonists for GPR109a and GPR109b, resulting in identification of compounds with improved activity at these receptors.
Asunto(s)
Furanos/síntesis química , Niacina/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Línea Celular , AMP Cíclico/biosíntesis , Furanos/química , Furanos/farmacología , Humanos , Niacina/farmacología , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
1-Substituted benzotriazole carboxylic acids have been identified as the first reported examples of selective small-molecule agonists of the human orphan G-protein-coupled receptor GPR109b (HM74), a low-affinity receptor for the HDL-raising drug niacin. No activity was observed at the highly homologous high-affinity niacin receptor GPR109a (HM74A). The high degree of selectivity was attributed to a difference in the amino acid sequence adjacent to a key arginine-ligand interaction allowing somewhat larger ligands to be tolerated by GPR109b.