ABSTRACT
Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis. Currently a number of Aurora kinase inhibitors with different isoform selectivities are being evaluated in the clinic. Herein we report the discovery and characterization of 21c (AC014) and 21i (AC081), two structurally novel, potent, kinome-selective pan-Aurora inhibitors. In the human colon cancer cell line HCT-116, both compounds potently inhibit histone H3 phosphorylation and cell proliferation while inducing 8N polyploidy. Both compounds administered intravenously on intermittent schedules displayed potent and durable antitumor activity in a nude rat HCT-116 tumor xenograft model and exhibited good in vivo tolerability. Taken together, these data support further development of both 21c and 21i as potential therapeutic agents for the treatment of solid tumors and hematological malignancies.
Subject(s)
Acetanilides/chemical synthesis , Antineoplastic Agents/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Triazines/chemical synthesis , Acetanilides/pharmacokinetics , Acetanilides/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Aurora Kinase A , Aurora Kinases , Catalytic Domain , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Histones/metabolism , Humans , Models, Molecular , Neoplasm Transplantation , Phosphorylation , Protein Binding , Rats , Rats, Nude , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Transplantation, Heterologous , Triazines/pharmacokinetics , Triazines/pharmacologyABSTRACT
The design, synthesis, and SAR of a series of substituted spirohydantoins are described. Optimization of an in-house screening hit gave compounds that exhibited potent binding affinity and functional activity at MCH-R1.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Hydantoins/chemical synthesis , Receptors, Pituitary Hormone/antagonists & inhibitors , Spiro Compounds/chemical synthesis , Anti-Obesity Agents/pharmacology , Drug Design , Humans , Hydantoins/pharmacology , Kinetics , Protein Binding , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
A series of thienopyrimidinone bis-aminopyrrolidine ureas were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor-1. These compounds exhibit potent binding affinity (K(i)=3 nM) and good in vitro metabolic stability.
Subject(s)
Chemistry, Pharmaceutical/methods , Pyrrolidines/chemistry , Receptors, Somatostatin/antagonists & inhibitors , Urea/analogs & derivatives , Urea/chemistry , Animals , Cytochrome P-450 CYP2D6 Inhibitors , Drug Design , Humans , Inhibitory Concentration 50 , Kinetics , Mice , Models, Chemical , Molecular Conformation , Protein Binding , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Receptors, Pituitary Hormone/antagonists & inhibitors , Urea/analogs & derivatives , Animals , Molecular Structure , Pyrrolidines/chemistry , Rats , Receptors, Pituitary Hormone/metabolism , Structure-Activity Relationship , Urea/chemical synthesis , Urea/chemistry , Urea/pharmacologyABSTRACT
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.
Subject(s)
Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Urea/analogs & derivatives , Animals , Inhibitory Concentration 50 , Molecular Structure , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Rats , Receptors, Somatostatin/metabolism , Structure-Activity Relationship , Urea/chemical synthesis , Urea/chemistry , Urea/pharmacokinetics , Urea/pharmacologyABSTRACT
A novel series of bis-aminopyrrolidine ureas containing either a 4-biphenylcarboxmide or 5-phenyl-2-thiophenecarboxamide group have been identified as potent and functional antagonists of the melanin-concentrating hormone receptor-1. Syntheses and SAR are described, which led to the discovery of compounds with high binding affinity (Ki = 1 nM) for the receptor. Preliminary in vitro metabolic stability data are also reported for key compounds.
Subject(s)
Amides , Pyrrolidines , Receptors, Somatostatin/antagonists & inhibitors , Urea , Amides/chemical synthesis , Amides/pharmacology , Animals , Drug Design , Molecular Conformation , Molecular Weight , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Rats , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemical synthesis , Urea/pharmacologyABSTRACT
Ureas derived from two substituted 3-aminopyrrolidine subunits were prepared as constrained analogs of a linear lead compound and tested as antagonists of the MCH(1) receptor. The series was optimized for substitution and stereochemistry to generate a functional antagonist with a K(i) of 3.3 nM and IC(50) of 12 nM (GTPgammaS).
