ABSTRACT
We report the use of fragment screening and fragment based drug design to develop a PI3γ kinase fragment hit into a lead. Initial fragment hits were discovered by high concentration biochemical screening, followed by a round of virtual screening to identify additional ligand efficient fragments. These were developed into potent and ligand efficient lead compounds using structure guided fragment growing and merging strategies. This led to a potent, selective, and cell permeable PI3γ kinase inhibitor with good metabolic stability that was useful as a preclinical tool compound.
Subject(s)
Drug Discovery , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Cell Membrane Permeability/drug effects , Drug Stability , Models, Molecular , Structure-Activity RelationshipABSTRACT
The design and profile of a series of adamantyl-containing long acting beta(2)-adrenoreceptor agonists are described. An optimal pharmacokinetic profile of low oral bioavailability was combined with a strong pharmacology profile when assessed using a guinea pig trachea tissue model. A focus was then placed on developing a robust synthetic route to ensure rapid delivery of material for clinical trials.
Subject(s)
Adamantane/analogs & derivatives , Adamantane/pharmacology , Adrenergic beta-2 Receptor Agonists , Adrenergic beta-Agonists/pharmacology , Adamantane/pharmacokinetics , Administration, Inhalation , Adrenergic beta-Agonists/chemistry , Adrenergic beta-Agonists/pharmacokinetics , Animals , Guinea Pigs , Humans , Trachea/drug effectsABSTRACT
This paper describes the identification and optimization of a novel series of DFG-out binding p38 inhibitors as inhaled agents for the treatment of chronic obstructive pulmonary disease. Structure based drug design and "inhalation by design" principles have been applied to the optimization of the lead series exemplied by compound 1a. Analogues have been designed to be potent and selective for p38, with an emphasis on slow enzyme dissociation kinetics to deliver prolonged lung p38 inhibition. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimize systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance and glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimize drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity, and solubility were considered to ensure compatibility with a dry powder inhaler. 1ab (PF-03715455) was subsequently identified as a clinical candidate from this series with efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of COPD.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Azabicyclo Compounds/chemical synthesis , Methylurea Compounds/chemical synthesis , Pulmonary Disease, Chronic Obstructive/drug therapy , Pyrazoles/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Administration, Inhalation , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Azabicyclo Compounds/pharmacokinetics , Azabicyclo Compounds/pharmacology , Binding Sites , Cell Membrane Permeability , Crystallography, X-Ray , Dogs , Drug Stability , Humans , In Vitro Techniques , Kinetics , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Methylurea Compounds/pharmacokinetics , Methylurea Compounds/pharmacology , Models, Molecular , Protein Binding , Protein Conformation , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Solubility , Surface Plasmon Resonance , Tumor Necrosis Factor-alpha/biosynthesis , p38 Mitogen-Activated Protein Kinases/chemistryABSTRACT
A novel series of potent and selective sulfonamide derived ß(2)-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties was achieved through targeted introduction of a phenolic moiety to support rapid phase II clearance, thereby minimizing systemic exposure following inhalation and reducing systemically mediated adverse events. Compound 38 (PF-610355) is identified as a clinical candidate from this series, with in vivo duration of action studies confirming its potential for once-daily use in humans. Compound 38 is currently in advanced phase II clinical studies.
Subject(s)
Adrenergic beta-2 Receptor Agonists , Adrenergic beta-Agonists/chemical synthesis , Asthma/drug therapy , Benzeneacetamides/chemical synthesis , Pulmonary Disease, Chronic Obstructive/drug therapy , Sulfonamides/chemical synthesis , Administration, Inhalation , Adrenergic beta-Agonists/pharmacokinetics , Adrenergic beta-Agonists/pharmacology , Animals , Benzeneacetamides/pharmacokinetics , Benzeneacetamides/pharmacology , Bronchoconstriction/drug effects , CHO Cells , Cricetinae , Cricetulus , Crystallography, X-Ray , Dogs , Female , Guinea Pigs , Hepatocytes/metabolism , Humans , In Vitro Techniques , Liver/metabolism , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Muscle, Smooth/drug effects , Muscle, Smooth/physiopathology , Rats , Stereoisomerism , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Trachea/drug effects , Trachea/metabolism , Trachea/physiopathologyABSTRACT
The use of three orthogonally tagged phosphine reagents to assist chemical work-up via phase-switch scavenging in conjunction with a modular flow reactor is described. These techniques (acidic, basic and Click chemistry) are used to prepare various amides and tri-substituted guanidines from in situ generated iminophosphoranes.
ABSTRACT
The design and profile of a series of saligenin containing long acting beta(2)-adrenoreceptor agonists is described. Evaluation of these analogues using a guinea-pig tissue model demonstrates that analogues within this series have significantly longer durations of action than salmeterol and have the potential for a once daily profile in human.
Subject(s)
Adrenergic beta-1 Receptor Agonists , Adrenergic beta-Agonists/pharmacology , Animals , Caco-2 Cells , Humans , MiceABSTRACT
The design and profile of a series of indole containing long acting beta(2)-adrenoceptor agonists is described. Evaluation of these analogues using an in vitro guinea pig trachea tissue model demonstrates that analogues within this series have salmeterol-like duration of action with potential for long duration of action in humans.
Subject(s)
Adrenergic beta-Agonists/chemistry , Adrenergic beta-Agonists/pharmacology , Asthma/drug therapy , Indoles/chemistry , Indoles/pharmacology , Pulmonary Disease, Chronic Obstructive/drug therapy , Receptors, Adrenergic, beta-2/drug effects , Adrenergic beta-Agonists/pharmacokinetics , Albuterol/analogs & derivatives , Albuterol/chemistry , Albuterol/pharmacology , Animals , Biological Availability , CHO Cells , Caco-2 Cells , Cricetinae , Cricetulus , Drug Design , Drug Evaluation, Preclinical , Guinea Pigs , Humans , Indoles/pharmacokinetics , Microsomes/drug effects , Microsomes/metabolism , Models, Molecular , Molecular Structure , Rats , Salmeterol Xinafoate , Time Factors , Trachea/drug effectsABSTRACT
In this paper we wish to report on a variety of expedient chemical transformations and purifications achieved via a generic "catch and release" methodology, based on a synthetically inert bipyridyl chelating tag that can be selectively captured with a resin-bound copper(II) species. Utilising this approach we are able to derive many of the same benefits associated with both solid phase synthesis and supported reagent methods.