RÉSUMÉ
Migration of immune cells to sites of inflammation is a critical step in the body's response to infections but also during autoimmune flares. Chemokine receptors, members of the GPCR receptors, are instrumental in directing specific cell types to their target organs. Herein, we describe a highly potent small molecule antagonist of the chemokine receptor CCR6, which came out of fine-tuned structural elaborations from a proprietary HTS hit. Three main issues in the parent chemical series-cytotoxicity, phototoxicity, and hERG, were successfully solved. Biological characterization demonstrated that compound 45 (IDOR-1117-2520) is a selective and insurmountable antagonist of CCR6. In vivo proof-of-mechanism studies in a mouse lung inflammation model using a representative compound from the chemical class of 45 confirmed that the targeted CCR6+ cells were efficiently inhibited from migrating into the bronchoalveoli. Finally, ADMET and physicochemical properties were well balanced and the preclinical package warranted progress in the clinic.
Sujet(s)
Maladies auto-immunes , Récepteurs CCR6 , Récepteurs CCR6/antagonistes et inhibiteurs , Récepteurs CCR6/métabolisme , Animaux , Humains , Maladies auto-immunes/traitement médicamenteux , Souris , Relation structure-activité , Découverte de médicamentRÉSUMÉ
The chemokine receptor CXCR7, also known as ACKR3, is a seven-transmembrane G-protein-coupled receptor (GPCR) involved in various pathologies such as neurological diseases, autoimmune diseases, and cancers. By binding and scavenging the chemokines CXCL11 and CXCL12, CXCR7 regulates their extracellular levels. From an original high-throughput screening campaign emerged hit 3 among others. The hit-to-lead optimization led to the discovery of a novel chemotype series exemplified by the trans racemic compound 11i. This series provided CXCR7 antagonists that block CXCL11- and CXCL12-induced ß-arrestin recruitment. Further structural modifications on the trisubstituted piperidine scaffold of 11i yielded compounds with high CXCR7 antagonistic activities and balanced ADMET properties. The effort described herein culminated in the discovery of ACT-1004-1239 (28f). Biological characterization of ACT-1004-1239 demonstrated that it is a potent, insurmountable antagonist. Oral administration of ACT-1004-1239 in mice up to 100 mg/kg led to a dose-dependent increase of plasma CXCL12 concentration.
Sujet(s)
Pipéridines/composition chimique , Récepteurs CXCR/antagonistes et inhibiteurs , Administration par voie orale , Amides/composition chimique , Amines/composition chimique , Animaux , Chimiokine CXCL12/sang , Cristallographie aux rayons X , Chiens , Évaluation préclinique de médicament , Période , Humains , Concentration inhibitrice 50 , Souris , Conformation moléculaire , Pipéridines/métabolisme , Pipéridines/pharmacocinétique , Liaison aux protéines , Rats , Récepteurs CXCR/génétique , Récepteurs CXCR/métabolisme , Relation structure-activitéRÉSUMÉ
The discovery of a new series of piperidine-based renin inhibitors is described herein. SAR optimization upon the P3 renin sub-pocket is described, leading to the discovery of 9 and 41, two bioavailable renin inhibitors orally active at low doses in a transgenic rat model of hypertension.
Sujet(s)
Antienzymes/synthèse chimique , Antienzymes/pharmacologie , Pipéridines/synthèse chimique , Pipéridines/pharmacologie , Rénine/antagonistes et inhibiteurs , Animaux , Antihypertenseurs/pharmacologie , Pression sanguine/effets des médicaments et des substances chimiques , Cytochrome P-450 CYP3A , Inhibiteurs des enzymes du cytochrome P-450 , Conception de médicament , Modèles moléculaires , Pipéridines/composition chimique , Conformation des protéines , Rats , Relation structure-activité , Diffraction des rayons XRÉSUMÉ
The optimization of the 4-position of recently described new 3,4-disubstituted piperidine-based renin inhibitors is reported herein. The synthesis and characterization of compounds leading to the discovery of 11 (ACT-178882, MK-1597), a renin inhibitor with a suitable profile for development is described.
Sujet(s)
Antienzymes/synthèse chimique , Antienzymes/pharmacologie , Pipéridines/synthèse chimique , Pipéridines/pharmacologie , Rénine/antagonistes et inhibiteurs , Angiotensinogène/génétique , Animaux , Animal génétiquement modifié , Cytochrome P-450 CYP3A , Inhibiteurs des enzymes du cytochrome P-450 , Antienzymes/composition chimique , Humains , Indicateurs et réactifs , Modèles moléculaires , Pipéridines/composition chimique , Rats , Rénine/génétique , Stéréoisomérie , Relation structure-activitéRÉSUMÉ
The discovery and SAR of a new series of substituted amino propanamide renin inhibitors are herein described. This work has led to the preparation of compounds with in vitro and in vivo profiles suitable for further development. Specifically, challenges pertaining to oral bioavailability, covalent binding and time-dependent CYP 3A4 inhibition were overcome thereby culminating in the identification of compound 50 as an optimized renin inhibitor with good efficacy in the hypertensive double-transgenic rat model.
Sujet(s)
Antihypertenseurs/composition chimique , Antihypertenseurs/usage thérapeutique , Hypertension artérielle/traitement médicamenteux , Rénine/antagonistes et inhibiteurs , Rénine/métabolisme , Animaux , Antihypertenseurs/pharmacologie , Pression sanguine/effets des médicaments et des substances chimiques , Cristallographie aux rayons X , Chiens , Humains , Modèles moléculaires , Liaison aux protéines , Rats , Rat Sprague-Dawley , Rénine/composition chimique , Relation structure-activitéRÉSUMÉ
New classes of de novo designed renin inhibitors are reported. Some of these compounds display excellent in vitro and in vivo activities toward human renin in a TGR model. The synthesis of these new types of mono- and bicyclic scaffolds are reported, and properties of selected compounds discussed.
Sujet(s)
Composés bicycliques pontés/classification , Composés bicycliques pontés/pharmacologie , Antienzymes/classification , Antienzymes/pharmacologie , Rénine/antagonistes et inhibiteurs , Composés bicycliques pontés/composition chimique , Cristallographie aux rayons X , Conception de médicament , Antienzymes/composition chimique , Humains , Modèles moléculaires , Structure moléculaire , Stéréoisomérie , Relation structure-activitéRÉSUMÉ
Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.
Sujet(s)
Composés azabicycliques/synthèse chimique , Composés azabicycliques/pharmacologie , Conception de médicament , Antienzymes/synthèse chimique , Antienzymes/pharmacologie , Rénine/antagonistes et inhibiteurs , Sites de fixation , Cristallographie aux rayons X , Relation dose-effet des médicaments , Antienzymes/composition chimique , Modèles moléculaires , Conformation moléculaire , Relation structure-activitéRÉSUMÉ
The malaria parasite Plasmodium falciparum degrades host cell hemoglobin inside an acidic food vacuole during the blood stage of the infectious cycle. A number of aspartic proteinases called plasmepsins (PMs) have been identified to play important roles in this degradation process and therefore generated significant interest as new antimalarial targets. Several x-ray structures of PMII have been described previously, but thus far, structure-guided drug design has been hampered by the fact that only inhibitors comprising a statine moiety or derivatives thereof have been published. Our drug discovery efforts to find innovative, cheap, and easily synthesized inhibitors against aspartic proteinases yielded some highly potent non-peptidic achiral inhibitors. A highly resolved (1.6 A) x-ray structure of PMII is presented, featuring a potent achiral inhibitor in an unprecedented orientation, contacting the catalytic aspartates indirectly via the "catalytic" water. Major side chain rearrangements in the active site occur, which open up a new pocket and allow a new binding mode of the inhibitor. Moreover, a second inhibitor molecule could be located unambiguously in the active site of PMII. These newly obtained structural insights will further guide our attempts to improve compound properties eventually leading to the identification of molecules suitable as antimalarial drugs.