ABSTRACT
A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.
Subject(s)
Indoles/chemistry , Indoles/pharmacology , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Crystallography, X-Ray , Indazoles/chemistry , Indazoles/pharmacology , JNK Mitogen-Activated Protein Kinases/chemistry , Phosphorylation , Structure-Activity RelationshipABSTRACT
A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC(50)=16 and 66 nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation.
Subject(s)
JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , Animals , Crystallography, X-Ray , Drug Design , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Models, Molecular , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Rats , Structure-Activity Relationship , Triazoles/chemical synthesisABSTRACT
The Janus kinases (JAKs) are involved in multiple signaling networks relevant to inflammatory diseases, and inhibition of one or more members of this class may modulate disease activity or progression. We optimized a new inhibitor scaffold, 3-amido-5-cyclopropylpyrrolopyrazines, to a potent example with reasonable kinome selectivity, including selectivity for JAK3 versus JAK1, and good biopharmaceutical properties. Evaluation of this analogue in cellular and in vivo models confirmed functional selectivity for modulation of a JAK3/JAK1-dependent IL-2 stimulated pathway over a JAK1/JAK2/Tyk2-dependent IL-6 stimulated pathway.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Cyclopropanes/chemical synthesis , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 3/antagonists & inhibitors , Pyrazines/chemical synthesis , Pyrroles/chemical synthesis , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Caco-2 Cells , Crystallography, X-Ray , Cyclopropanes/pharmacokinetics , Cyclopropanes/pharmacology , Gene Knockdown Techniques , High-Throughput Screening Assays , Humans , Interleukin-2/physiology , Janus Kinase 1/genetics , Janus Kinase 1/metabolism , Janus Kinase 3/genetics , Janus Kinase 3/metabolism , Mice , Models, Molecular , Pyrazines/pharmacokinetics , Pyrazines/pharmacology , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , RNA, Small Interfering/genetics , Rats , Receptors, Interleukin-6/physiology , Signal Transduction/drug effects , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/metabolismABSTRACT
The purinoceptor subtypes P2X(3) and P2X(2/3) have been shown to play a pivotal role in models of various pain conditions. Identification of a potent and selective dual P2X(3)/P2X(2/3) diaminopyrimidine antagonist RO-4 prompted subsequent optimization of the template. This paper describes the SAR and optimization of the diaminopyrimidine ring and particularly the substitution of the 2-amino group. The discovery of the highly potent and drug-like dual P2X(3)/P2X(2/3) antagonist RO-51 is presented.
Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Chemistry, Pharmaceutical/methods , Pain/drug therapy , Purinergic P2 Receptor Antagonists , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Adenosine Triphosphate/chemistry , Animals , CHO Cells , Cricetinae , Cricetulus , Drug Design , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Models, Chemical , Receptors, Purinergic P2/chemistry , Structure-Activity RelationshipABSTRACT
P2X purinoceptors are ligand-gated ion channels whose endogenous ligand is ATP. Both the P2X(3) and P2X(2/3) receptor subtypes have been shown to play an important role in the regulation of sensory function and dual P2X(3)/P2X(2/3) antagonists offer significant potential for the treatment of pain. A high-throughput screen of the Roche compound collection resulted in the identification of a novel series of diaminopyrimidines; subsequent optimization resulted in the discovery of RO-4, a potent, selective and drug-like dual P2X(3)/P2X(2/3) antagonist.
Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Chemistry, Pharmaceutical/methods , Pain/drug therapy , Purinergic P2 Receptor Antagonists , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Adenosine Triphosphate/chemistry , Drug Design , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Ions , Ligands , Models, Chemical , Receptors, Purinergic P2/chemistry , Structure-Activity RelationshipABSTRACT
Replacement of the N-butyl side-chain of lead 5-HT4 receptor antagonist 2 with propanesulfonylpiperidinyl, morpholinyl, and piperazinyl groups led to higher affinity analogs 4-6. In vitro drug metabolism screens and cassette pharmacokinetic studies in the dog led to identification of the N-methylpiperazinyl analog (6b), which displayed pharmacokinetic, selectivity, and safety parameters sufficient for advancement to the clinic for the treatment of urinary incontinence.
