ABSTRACT
Optimization of pyridine-based noncatalytic site integrase inhibitors (NCINIs) based on compound 2 has led to the discovery of molecules capable of inhibiting virus harboring N124 variants of HIV integrase (IN) while maintaining minimal contribution of enterohepatic recirculation to clearance in rat. Structure-activity relationships at the C6 position established chemical space where the extent of enterohepatic recirculation in the rat is minimized. Desymmetrization of the C4 substituent allowed for potency optimization against virus having the N124 variant of integrase. Combination of these lessons led to the discovery of compound 20, having balanced serum-shifted antiviral potency and minimized excretion in to the biliary tract in rat, potentially representing a clinically viable starting point for a new treatment option for individuals infected with HIV.
ABSTRACT
A high-throughput screen based on a viral replication assay was used to identify inhibitors of the human cytomegalovirus. Using this approach, hit compound 1 was identified as a 4 µM inhibitor of HCMV that was specific and selective over other herpes viruses. Time of addition studies indicated compound 1 exerted its antiviral effect early in the viral life cycle. Mechanism of action studies also revealed that this series inhibited infection of MRC-5 and ARPE19 cells by free virus and via direct cell-to-cell spread from infected to uninfected cells. Preliminary structure-activity relationships demonstrated that the potency of compound 1 could be improved to a low nanomolar level, but metabolic stability was a key optimization parameter for this series. A strategy focused on minimizing metabolic hydrolysis of the N1-amide led to an alternative scaffold in this series with improved metabolic stability and good pharmacokinetic parameters in rat.
ABSTRACT
Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models.
Subject(s)
Phenylurea Compounds/chemistry , Platelet Aggregation Inhibitors/chemistry , Purinergic P2Y Receptor Antagonists/chemistry , Receptors, Purinergic P2Y1/chemistry , Thiazoles/chemistry , Urea/analogs & derivatives , Administration, Oral , Animals , Dogs , Half-Life , Macaca fascicularis , Phenylurea Compounds/pharmacokinetics , Phenylurea Compounds/pharmacology , Phenylurea Compounds/therapeutic use , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation Inhibitors/therapeutic use , Purinergic P2Y Receptor Antagonists/pharmacokinetics , Purinergic P2Y Receptor Antagonists/pharmacology , Purinergic P2Y Receptor Antagonists/therapeutic use , Rats , Receptors, Purinergic P2Y1/metabolism , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Thiazoles/therapeutic use , Thrombosis/drug therapy , Urea/pharmacokinetics , Urea/pharmacology , Urea/therapeutic useABSTRACT
A number of new amine scaffolds with good inhibitory activity in the ADP-induced platelet aggregation assay have been found to be potent antagonists of the P2Y1 receptor. SAR optimization led to the identification of isoindoline 3c and piperidine 4a which showed good in vitro binding and functional activities, as well as improved aqueous solubility. Among them, the piperidine 4a showed the best overall profile with favorable PK parameters.
Subject(s)
Amines/chemistry , Purinergic P2Y Receptor Agonists/chemistry , Receptors, Purinergic P2Y1/chemistry , Urea/analogs & derivatives , Adenosine Diphosphate/pharmacology , Amines/chemical synthesis , Amines/pharmacokinetics , Animals , Blood Platelets/drug effects , Blood Platelets/metabolism , Half-Life , Humans , Microsomes, Liver/metabolism , Piperidines/chemistry , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacokinetics , Protein Binding , Purinergic P2Y Receptor Agonists/chemical synthesis , Purinergic P2Y Receptor Agonists/pharmacokinetics , Rats , Receptors, Purinergic P2Y1/metabolism , Structure-Activity Relationship , Urea/chemical synthesis , Urea/pharmacokineticsABSTRACT
Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.
Subject(s)
Drug Design , Molecular Conformation , Phenylurea Compounds/pharmacology , Phenylurea Compounds/pharmacokinetics , Purinergic P2Y Receptor Antagonists/pharmacology , Purinergic P2Y Receptor Antagonists/pharmacokinetics , Receptors, Purinergic P2Y1/metabolism , Spiro Compounds/pharmacology , Spiro Compounds/pharmacokinetics , Urea/pharmacology , Urea/pharmacokinetics , Animals , Biological Availability , Humans , Indoles/chemistry , Models, Molecular , Phenylurea Compounds/chemistry , Phenylurea Compounds/metabolism , Purinergic P2Y Receptor Antagonists/chemistry , Purinergic P2Y Receptor Antagonists/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Purinergic P2Y1/chemistry , Sequence Homology, Amino Acid , Spiro Compounds/chemistry , Spiro Compounds/metabolism , Urea/chemistry , Urea/metabolismABSTRACT
Five-membered-ring heterocyclic urea mimics have been found to be potent and selective antagonists of the P2Y1 receptor. SAR of the various heterocyclic replacements is presented, as well as side-chain SAR of the more potent thiadiazole ring system which leads to thiadiazole 4c as a new antiplatelet agent.
Subject(s)
Purinergic P2Y Receptor Antagonists/chemistry , Purinergic P2Y Receptor Antagonists/pharmacology , Receptors, Purinergic P2Y1/chemistry , Thiadiazoles/chemistry , Thiadiazoles/pharmacology , Biomimetic Materials/chemistry , Biomimetic Materials/pharmacology , Humans , Kinetics , Protein Binding , Structure-Activity Relationship , Urea/chemistryABSTRACT
We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure-activity relationship studies, biochemical potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical in vivo activity against human tumor xenograft models.