RÉSUMÉ
A novel series of annulated tricyclic compounds was synthesized and evaluated as NMDA/NR2B antagonists. Structure-activity development was directed towards in vitro optimization of NR2B activity and selectivity over the hERG K(+) channel. Preferred compounds were subsequently evaluated for selectivity in an alpha(1)-adrenergic receptor binding counter-screen and a cell-based assay of NR2B activity.
Sujet(s)
Benzocycloheptènes/synthèse chimique , Agents neuromédiateurs/synthèse chimique , Pyridines/synthèse chimique , Récepteurs du N-méthyl-D-aspartate/antagonistes et inhibiteurs , Benzocycloheptènes/composition chimique , Benzocycloheptènes/pharmacologie , Lignée cellulaire , Canaux potassiques éther-à-go-go/métabolisme , Humains , Agents neuromédiateurs/composition chimique , Agents neuromédiateurs/pharmacologie , Pyridines/composition chimique , Pyridines/pharmacologie , Récepteurs du N-méthyl-D-aspartate/métabolisme , Relation structure-activitéRÉSUMÉ
A series of 10-hydroxy-7,8-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-diones was synthesized and tested for their inhibition of HIV-1 replication in cell culture. Structure-activity studies indicated that high antiviral potency against wild-type virus as well as viruses containing integrase mutations that confer resistance to three different structural classes of integrase inhibitors could be achieved by incorporation of small aliphatic groups at certain positions on the core template. An optimal compound from this study, 16, inhibits integrase strand-transfer activity with an IC(50) value of 10 nM, inhibits HIV-1 replication in cell culture with an IC(95) value of 35 nM in the presence of 50% normal human serum, and displays modest pharmacokinetic properties in rats (i.v. t(1/2)=5.3 h, F=17%).
Sujet(s)
Chimie pharmaceutique/méthodes , Intégrase du VIH/synthèse chimique , Intégrase du VIH/pharmacologie , Integrases/génétique , Mutation , Administration par voie orale , Animaux , Antiviraux/pharmacologie , Biodisponibilité , Conception de médicament , Humains , Concentration inhibitrice 50 , Modèles chimiques , Rats , Relation structure-activité , Réplication viraleRÉSUMÉ
A series of 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamides was synthesized and tested for their inhibition of HIV-1 integrase catalytic activity and HIV-1 replication in cells. Structure-activity studies around lead compound 5 indicated that a coplanar relationship of metal-binding heteroatoms provides optimal binding to the integrase active site. Identification of potency-enhancing substituents and adjustments in lipophilicity provided 17b which inhibits integrase-catalyzed strand transfer with an IC(50) value of 74 nM and inhibits HIV-1 replication in cell culture in the presence of 50% normal human serum with an IC(95) value of 63 nM.
Sujet(s)
Inhibiteurs de l'intégrase du VIH/composition chimique , Inhibiteurs de l'intégrase du VIH/pharmacologie , Intégrase du VIH/effets des médicaments et des substances chimiques , Pyrazines/composition chimique , Pyrazines/pharmacologie , Catalyse , Lignée cellulaire , Intégrase du VIH/métabolisme , Inhibiteurs de l'intégrase du VIH/synthèse chimique , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/enzymologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/physiologie , Pyrazines/synthèse chimique , Relation structure-activité , Réplication virale/effets des médicaments et des substances chimiquesRÉSUMÉ
The human immunodeficiency virus type-1 (HIV-1) encodes three enzymes essential for viral replication: a reverse transcriptase, a protease, and an integrase. The latter is responsible for the integration of the viral genome into the human genome and, therefore, represents an attractive target for chemotherapeutic intervention against AIDS. A drug based on this mechanism has not yet been approved. Benzyl-dihydroxypyrimidine-carboxamides were discovered in our laboratories as a novel and metabolically stable class of agents that exhibits potent inhibition of the HIV integrase strand transfer step. Further efforts led to very potent compounds based on the structurally related N-Me pyrimidone scaffold. One of the more interesting compounds in this series is the 2-N-Me-morpholino derivative 27a, which shows a CIC95 of 65 nM in the cell in the presence of serum. The compound has favorable pharmacokinetic properties in three preclinical species and shows no liabilities in several counterscreening assays.
Sujet(s)
Inhibiteurs de l'intégrase du VIH/synthèse chimique , Intégrase du VIH/composition chimique , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/effets des médicaments et des substances chimiques , Morpholines/synthèse chimique , Pyrimidinones/synthèse chimique , Administration par voie orale , Animaux , Biodisponibilité , Protéines du sang/métabolisme , Lignée cellulaire tumorale , Chiens , Inhibiteurs de l'intégrase du VIH/pharmacocinétique , Inhibiteurs de l'intégrase du VIH/pharmacologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/enzymologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/physiologie , Humains , Macaca mulatta , Morpholines/pharmacocinétique , Morpholines/pharmacologie , Liaison aux protéines , Pyrimidinones/pharmacocinétique , Pyrimidinones/pharmacologie , Rats , Stéréoisomérie , Relation structure-activité , Réplication virale/effets des médicaments et des substances chimiquesRÉSUMÉ
This study used behavioural and in vivo electrophysiological paradigms to examine the effects of systemic and spinal administration of a bradykinin B1 receptor antagonist, compound X, on acute nociceptive responses in the rat. In behavioural experiments, compound X significantly increased the latency to withdraw the hindpaw from a radiant heat source after both intravenous and intrathecal administration, without affecting motor performance on the rotarod. In electrophysiological experiments, both intravenous and direct spinal administration of compound X attenuated the responses of single dorsal horn neurones to noxious thermal stimulation of the hindpaw. These data show that the antinociceptive effects of a bradykinin B1 receptor antagonist are mediated, at least in part, at the level of the spinal cord and suggest a role for spinal bradykinin B1 receptors in acute nociception.
Sujet(s)
Amides/pharmacocinétique , Antagonistes du récepteur B1 de la bradykinine , Naphtalènes/pharmacocinétique , Mesure de la douleur/méthodes , Pyrrolidines/pharmacocinétique , Moelle spinale/effets des médicaments et des substances chimiques , Amides/administration et posologie , Animaux , Carragénane/administration et posologie , Carragénane/toxicité , Modèles animaux de maladie humaine , Relation dose-effet des médicaments , Électrophysiologie/méthodes , Pied , Membre pelvien , Température élevée/effets indésirables , Hyperalgésie/étiologie , Hyperalgésie/physiopathologie , Hyperalgésie/prévention et contrôle , Hypersensibilité/étiologie , Hypersensibilité/physiopathologie , Injections veineuses , Injections rachidiennes , Mâle , Morphine/pharmacologie , Naphtalènes/administration et posologie , Nocicepteurs/effets des médicaments et des substances chimiques , Nocicepteurs/physiologie , Performance psychomotrice/effets des médicaments et des substances chimiques , Pyrrolidines/administration et posologie , Rats , Rat Sprague-Dawley , Moelle spinale/physiologieRÉSUMÉ
Introduction of a 5,6-dihydrouracil functionality in the 5-position of N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide 1 led to a series of highly active HIV-1 integrase inhibitors. These compounds displayed low nanomolar activity in inhibiting both the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 11 is a 150-fold more potent antiviral agent than 1, with a CIC(95) of 40 nM in the presence of human serum. It displays good pharmacokinetics when dosed in rats and dogs.
Sujet(s)
Composés benzyliques/pharmacologie , Inhibiteurs de l'intégrase du VIH/pharmacologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/effets des médicaments et des substances chimiques , Naphtyridines/pharmacologie , Uracile/analogues et dérivés , Réplication virale/effets des médicaments et des substances chimiques , Animaux , Composés benzyliques/composition chimique , Composés benzyliques/pharmacocinétique , Biodisponibilité , Cristallographie aux rayons X , Inhibiteurs de l'intégrase du VIH/composition chimique , Inhibiteurs de l'intégrase du VIH/pharmacocinétique , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/physiologie , Naphtyridines/composition chimique , Naphtyridines/pharmacocinétique , Rats , Uracile/composition chimiqueRÉSUMÉ
Optimization of a previously reported thrombin inhibitor, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-trans-4-aminocyclohexylmethylamide (1), by replacing the aminocyclohexyl P1 group provided a new lead structure, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-2-aminomethyl-5-chlorobenzylamide (2), with improved potency (K(i) = 0.49 nM for human thrombin, 2x APTT = 0.37 microM in human plasma) and pharmacokinetic properties (F = 39%, iv T(1/2) = 13 h in dogs). An effective strategy for reducing plasma protein binding of 2 and improving efficacy in an in vivo thrombosis model in rats was to replace the lipophilic fluorenyl group in P3 with an azafluorenyl group. Systematic investigation of all possible azafluorenyl P3 isomers and azafluorenyl-N-oxide analogues of 2 led to the identification of an optimal compound, 3-aza-9-hydroxyfluoren-9(R)-ylcarbonyl-l-prolyl-2-aminomethyl-5-chlorobenzylamide (19b), with high potency (K(i) = 0.40 nM, 2x APTT = 0.18 microM), excellent pharmacokinetic properties (F = 55%, T(1/2) = 14 h in dogs), and complete efficacy in the in vivo thrombosis model in rats (inhibition of FeCl(3)-induced vessel occlusions in six of six rats receiving an intravenous infusion of 10 microg/kg/min of 19b). The stereochemistry of the azafluorenyl group in 19b was determined by X-ray crystallographic analysis of its N-oxide derivative (23b) bound in the active site of human thrombin.
Sujet(s)
Fluorènes/synthèse chimique , Proline/analogues et dérivés , Proline/synthèse chimique , Thrombine/antagonistes et inhibiteurs , Administration par voie orale , Animaux , Biodisponibilité , Protéines du sang/métabolisme , Cristallographie aux rayons X , Chiens , Fluorènes/composition chimique , Fluorènes/pharmacologie , Période , Humains , Techniques in vitro , Macaca mulatta , Mâle , Microsomes du foie/métabolisme , Modèles moléculaires , Proline/composition chimique , Proline/pharmacologie , Liaison aux protéines , Rats , Rat Sprague-Dawley , Stéréoisomérie , Relation structure-activitéRÉSUMÉ
Antagonism of the bradykinin B(1) receptor was demonstrated to be a potential treatment for chronic pain and inflammation. Novel benzodiazepines were designed that display subnanomolar affinity for the bradykinin B(1) receptor (K(i) = 0.59 nM) and high selectivity against the bradykinin B(2) receptor (K(i) > 10 microM). In vivo efficacy, comparable to morphine, was demonstrated for lead compounds in a rodent hyperalgesia model.
Sujet(s)
Benzodiazépines/synthèse chimique , Antagonistes des récepteurs de la bradykinine , Animaux , Benzodiazépines/composition chimique , Benzodiazépines/pharmacologie , Cellules CHO , Cricetinae , Humains , Hyperalgésie/induit chimiquement , Hyperalgésie/traitement médicamenteux , Dosage par compétition , Rats , Rat Sprague-Dawley , Récepteur de la bradykinine de type B1 , Récepteur de la bradykinine de type B2 , Relation structure-activitéRÉSUMÉ
Addition of the Reformatsky reagent derived from ethyl bromodifluoroacetate to alkyl- and aryl-substituted N-tert-butylsulfinimines furnishes beta-tert-butylsulfinamyl-beta-substituted alpha,alpha-difluoroproponiates in diastereomeric ratios ranging from 80:20 to 95:5. The diastereomers are easily separated and the enantiomerically pure, protected beta-amino esters are readily transformed to the corresponding acid, amide, and amine derivatives as useful synthons for medicinal chemistry targets.
Sujet(s)
Acides aminés/synthèse chimique , Fluor , Imines , Stéréoisomérie , Sulfonamides/composition chimiqueRÉSUMÉ
A series of novel, highly potent alpha(v)beta(3) receptor antagonists with favorable pharmacokinetic profiles has been identified. In this series of antagonists, 2-aryl beta-amino acids function as potent aspartic acid replacements.
Sujet(s)
Acides aminés/composition chimique , Esters/composition chimique , Récepteur vitronectine/antagonistes et inhibiteurs , Acides aminés/synthèse chimique , Acides aminés/pharmacocinétique , Animaux , Acide aspartique/composition chimique , Matériaux biomimétiques/synthèse chimique , Matériaux biomimétiques/composition chimique , Matériaux biomimétiques/pharmacocinétique , Chiens , Évaluation préclinique de médicament , Esters/synthèse chimique , Esters/pharmacocinétique , Humains , Concentration inhibitrice 50 , Oligopeptides/composition chimique , Oligopeptides/pharmacocinétique , Liaison aux protéines , Récepteur vitronectine/métabolisme , Relation structure-activitéRÉSUMÉ
A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synthesized. Compared with previously described linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined improved pharmacokinetic properties with a reduced potential for side effects. In dogs, oral bioavailability was good to excellent, and increases in plasma half-life were due to attenuated clearance. It was observed that in vivo clearance correlated with the flexibility of the molecules and this concept proved useful in the design of FTIs that exhibited low clearance, such as FTI 78. X-ray crystal structures of compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they provide details of the key interactions in such ternary complexes. Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.