RÉSUMÉ
Neuropsychiatric disorders such as major depressive disorders and schizophrenia are often associated with disruptions to the normal 24 h sleep wake cycle. Casein kinase 1 (CK1δ) is an integral part of the molecular machinery that regulates circadian rhythms. Starting from a cluster of bicyclic pyrazoles identified from a virtual screening effort, we utilized structure-based drug design to identify and reinforce a unique "hinge-flip" binding mode that provides a high degree of selectivity for CK1δ versus the kinome. Pharmacokinetics, brain exposure, and target engagement as measured by ex vivo autoradiography are described for advanced analogs.
RÉSUMÉ
A method for the preparation of highly functionalized 4-iodo-7-azaindazoles is reported. These valuable heterocycles are synthesized via condensation of 2-hydrazineylpyrimidines with various iodoalkynones followed by Diels-Alder/retro-Diels-Alder cyclization. The method is general to the formation of products with a variety of C3, C5, and C6 substituents while preserving the C4 iodide functional handle for further late-stage functionalization. The utility of this transformation is demonstrated through the rapid synthesis of several bioactive azaindazole targets.
RÉSUMÉ
This report discloses the discovery and characterization of imidazo[1,2-a]pyrazines and pyrazolo[1,5-c]pyrimidines as selective negative modulators of α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) associated with transmembrane AMPAR regulatory protein γ-8. Imidazopyrazine 5 was initially identified as a promising γ-8 selective high-throughput screening hit, and subsequent structure-activity relationship optimization yielded subnanomolar, brain penetrant leads. Replacement of the imidazopyrazine core with an isosteric pyrazolopyrimidine scaffold improved microsomal stability and efflux liabilities to provide 26, JNJ-61432059. Following oral administration, 26 exhibited time- and dose-dependent AMPAR/γ-8 receptor occupancy in mouse hippocampus, which resulted in robust seizure protection in corneal kindling and pentylenetetrazole (PTZ) anticonvulsant models.
RÉSUMÉ
The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.
Sujet(s)
Découverte de médicament , Hydrocarbures fluorés/pharmacologie , Pyrimidines/pharmacologie , Récepteurs à la gonadolibérine/antagonistes et inhibiteurs , Animaux , Cellules Caco-2 , Inhibiteurs du cytochrome P-450 CYP3A , Évaluation préclinique de médicament , Humains , Hydrocarbures fluorés/composition chimique , Hydrocarbures fluorés/métabolisme , Macaca fascicularis , Mâle , Microsomes du foie/composition chimique , Microsomes du foie/métabolisme , Structure moléculaire , Pyrimidines/composition chimique , Pyrimidines/métabolisme , Stéréoisomérie , Relation structure-activité , Facteurs tempsRÉSUMÉ
The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC(50)s<10 nM), selective against the other monoamine transporters, weak CYP2D6 inhibitors (IC(50)s>1 microM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile.
Sujet(s)
Inhibiteurs du cytochrome P-450 CYP2D6 , Indanes/synthèse chimique , Indanes/pharmacologie , Inhibiteurs de la capture des neurotransmetteurs/synthèse chimique , Inhibiteurs de la capture des neurotransmetteurs/pharmacologie , Norépinéphrine/antagonistes et inhibiteurs , Chlorhydrate d'atomoxétine , Techniques de chimie combinatoire , Conception de médicament , Humains , Indanes/composition chimique , Concentration inhibitrice 50 , Microsomes du foie/métabolisme , Structure moléculaire , Inhibiteurs de la capture des neurotransmetteurs/composition chimique , Propylamines/pharmacologie , Stéréoisomérie , Relation structure-activitéRÉSUMÉ
The design, synthesis, and SAR of a series of ring-constrained norepinephrine reuptake inhibitors are described. A substantially rigid inhibitor with potent functional activity at the transporter (IC(50)=8 nM) was used to develop a model for the distance and orientation of key features necessary for interaction with the norepinephrine transporter (NET).
Sujet(s)
Inhibiteurs de la capture adrénergique/synthèse chimique , Inhibiteurs de la capture adrénergique/pharmacologie , Transporteurs de la norépinéphrine/synthèse chimique , Transporteurs de la norépinéphrine/pharmacologie , Amines/composition chimique , Chlorhydrate d'atomoxétine , Sites de fixation , Lignée cellulaire , Chimie pharmaceutique/méthodes , Désipramine/composition chimique , Conception de médicament , Humains , Concentration inhibitrice 50 , Modèles chimiques , Conformation moléculaire , Propylamines/composition chimique , Relation structure-activitéRÉSUMÉ
Optimization of a series of uracils bearing a 2-fluoro- or 2-chloro-3-methoxyphenyl group at the 5-position resulted in compounds such as 3d and 3f with subnanomolar binding affinity at the human GnRH receptor. While the 2-fluoro-3-methoxyphenyl compound 3a was characterized as a mixture of interchangeable atropisomers, the diastereoisomers of 2-chloro-3-methoxyphenyl analogs were separated. It was found that the aR-atropisomer was much more potent than the aS-isomer based on the X-ray crystal structure of 3h-II.
Sujet(s)
Récepteurs à la gonadolibérine/antagonistes et inhibiteurs , Uracile/analogues et dérivés , Uracile/synthèse chimique , Uracile/pharmacologie , Cristallographie aux rayons X , Humains , Conformation moléculaire , Structure moléculaire , Stéréoisomérie , Relation structure-activité , Uracile/composition chimiqueRÉSUMÉ
Incorporation of a carboxylic acid into a series of uracil derivatives as hGnRH-R antagonists resulted in a significant reduction of CYP3A4 inhibitory activity. Highly potent hGnRH antagonists with low CYP3A4 inhibitory liability, such as 8a and 8d, were identified. Thus, 8a had a K(i) of 2.2 nM at GnRH-R and an IC(50) of 36 microM at CYP3A4.
Sujet(s)
Inhibiteurs du cytochrome P-450 CYP3A , Hormone de libération des gonadotrophines/antagonistes et inhibiteurs , Récepteurs à la gonadolibérine/antagonistes et inhibiteurs , Uracile/analogues et dérivés , Uracile/synthèse chimique , Animaux , Cytochrome P-450 CYP3A , Haplorhini , Humains , Concentration inhibitrice 50 , Structure moléculaire , Rats , Relation structure-activité , Uracile/pharmacocinétiqueRÉSUMÉ
The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited potent binding affinity and functional activity at MCH-R1, and good oral bioavailability in rat.
Sujet(s)
Pyrrolidines/synthèse chimique , Pyrrolidines/pharmacologie , Récepteur hormone hypophysaire/antagonistes et inhibiteurs , Urée/analogues et dérivés , Animaux , Structure moléculaire , Pyrrolidines/composition chimique , Rats , Récepteur hormone hypophysaire/métabolisme , Relation structure-activité , Urée/synthèse chimique , Urée/composition chimique , Urée/pharmacologieRÉSUMÉ
The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited considerable binding affinity (Ki = 1 nM) and functional activity at MCH-R1, acceptable CYP2D6 inhibition, and good rat brain exposure.
Sujet(s)
Pyrrolidines/composition chimique , Pyrrolidines/pharmacologie , Récepteur somatostatine/antagonistes et inhibiteurs , Urée/analogues et dérivés , Animaux , Concentration inhibitrice 50 , Structure moléculaire , Pyrrolidines/synthèse chimique , Pyrrolidines/pharmacocinétique , Rats , Récepteur somatostatine/métabolisme , Relation structure-activité , Urée/synthèse chimique , Urée/composition chimique , Urée/pharmacocinétique , Urée/pharmacologieRÉSUMÉ
Several efficient synthetic routes for 2-, 4-, and 6-aryl-1,2,4-triazine-3,5-diones were developed. Derivatives were synthesized and studied as gonadotropin-releasing hormone antagonists in an effort to understand structure-activity relationships of the monocyclic compounds.
Sujet(s)
Récepteurs à la gonadolibérine/antagonistes et inhibiteurs , Triazines/synthèse chimique , Humains , Cétones/synthèse chimique , Cétones/pharmacologie , Liaison aux protéines , Relation structure-activité , Triazines/pharmacologieRÉSUMÉ
SAR studies of 1,3,5-triazine-2,4,6-triones as human gonadotropin-releasing hormone receptor antagonists resulted in potent compounds. The best compound from the series had a binding affinity of 2 nM.
Sujet(s)
Récepteurs à la gonadolibérine/antagonistes et inhibiteurs , Triazines/pharmacologie , Évaluation préclinique de médicament , Humains , Structure moléculaire , Relation structure-activité , Triazines/synthèse chimique , Triazines/composition chimiqueRÉSUMÉ
Uracil derivatives were designed and synthesized to avoid atropisomers observed in the 6-methyluracils as antagonists of the human GnRH receptor. Optimization at the 1- and 5-positions of the uracil resulted in potent compounds such as 24 (Ki=0.45 nM).
Sujet(s)
Récepteurs à la gonadolibérine/antagonistes et inhibiteurs , Uracile/pharmacologie , Humains , Isomérie , Structure moléculaire , Uracile/composition chimique , Diffraction des rayons XRÉSUMÉ
A convenient one-pot synthetic route was developed for the preparation of asymmetric 1,3-dialkyl-1,3,5-triazine-2,4,6-triones from readily available alkyl- or aryl-isocyanates, primary amines and N-chlorocarbonyl isocyanate in excellent yields. Subsequent alkylation with N-protected amino alcohols afforded the desired 1,3,5-triazine-2,4,6-triones in good yields. This methodology was applied to the synthesis of a chemical library acting as antagonists of the hGnRH receptor.
Sujet(s)
Cétones/synthèse chimique , Récepteurs à la gonadolibérine/antagonistes et inhibiteurs , Triazines/synthèse chimique , Alkylation , Techniques de chimie combinatoire , Humains , Liaison aux protéines , Relation structure-activitéRÉSUMÉ
The synthesis and SAR studies of thieno[2,3-d]pyrimidine-2,4-diones as human GnRH receptor antagonists to treat reproductive diseases are discussed. It was found that the 2-(2-pyridyl)ethyl group on the 5-aminomethyl functionality of the core structure was a key feature for good receptor binding activity. SAR study of the 6-(4-aminophenyl) group suggests that hydrophobic substituents were preferred. The best compound from this series had binding affinity (K(i)) of 0.4 nM to the human GnRH receptor.
Sujet(s)
Pyrimidinones/composition chimique , Pyrimidinones/pharmacologie , Récepteurs à la gonadolibérine/antagonistes et inhibiteurs , Thiophènes/composition chimique , Thiophènes/pharmacologie , Pyrimidinones/synthèse chimique , Relation structure-activité , Thiophènes/synthèse chimiqueRÉSUMÉ
SAR studies of 7-phenylpyrrolo[1,2-a]pyrimid-4-ones 1 and 2, and 2-phenylimidazolo[1,2-a]pyrimidines 3 and 4, as nonpeptide human GnRH receptor antagonists, lead us to believe that the aromatic ring at position-2 of 4 is no longer crucial for the binding once an aryl group is incorporated at postion-6. We report here the use of a 2-alkyl group on the imidazolo[1,2-a]pyrimidone core to generate potent GnRH receptor antagonists. This discovery enabled us to obtain smaller but equally potent GnRH receptor antagonists.