ABSTRACT
Using a novel physiologically relevant in vitro human whole blood neutrophil shape change assay, an aminopyrazine series of selective PI3Kγ inhibitors was identified and prioritized for further optimization. Severe solubility limitations associated with the series leading to low oral bioavailability and poor exposures, especially at higher doses, were overcome by moving to an aminopyridine core. Compound 33, with the optimal balance of on-target activity, selectivity, and pharmacokinetic parameters, progressed into in vivo studies and demonstrated good efficacy (10 mg/kg) in a rat model of airway inflammation. Sufficient exposures were achieved at high doses to support toxicological studies, where unexpected inflammatory cell infiltrates in cardiovascular tissue prevented further compound development.
Subject(s)
Aminopyridines/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Class Ib Phosphatidylinositol 3-Kinase/metabolism , Inflammation/drug therapy , Protein Kinase Inhibitors/therapeutic use , Aminopyridines/chemical synthesis , Aminopyridines/pharmacokinetics , Aminopyridines/toxicity , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/toxicity , Female , Humans , Molecular Structure , No-Observed-Adverse-Effect Level , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/toxicity , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Pyrazines/therapeutic use , Pyrazines/toxicity , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A series of inhibitors of Autotaxin (ATX) has been developed using the binding mode of known inhibitor, PF-8380, as a template. Replacement of the benzoxazolone with a triazole zinc-binding motif reduced crystallinity and improved solubility relative to PF-8380. Modification of the linker region removed hERG activity and led to compound 12 - a selective, high affinity, orally-bioavailable inhibitor of ATX. Compound 12 concentration-dependently inhibits autotaxin and formation of LPA in vivo, as shown in pharmacokinetic-pharmacodynamic experiments.
Subject(s)
Drug Design , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Triazoles/pharmacology , Administration, Oral , Animals , Benzoxazoles/pharmacology , Drug Stability , Humans , Male , Microsomes/metabolism , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacokinetics , Piperazines/pharmacology , Rats, Sprague-Dawley , Solubility , Triazoles/administration & dosage , Triazoles/chemical synthesis , Triazoles/pharmacokineticsABSTRACT
OBJECTIVES: Military personnel risk injury due to accidents, disasters, and military threats during Phase Zero "shaping" operations. Medical facilities must be poised to respond. METHODS: The U.S. Pacific Command (PACOM) Area of Responsibility (AOR) covers more than 50% of the earth's surface; relevant Clinical Practice Guidelines must include the maritime setting and extended evacuation periods. Military hospitals in the region are not connected by a defined Trauma System. There is variable adherence to trauma training requirements before assignment in this AOR. Demand for trauma care at any 1 location is low and trauma teams have little opportunity to maintain competency for high-risk/low-volume interventions. There is no documentation of total demand for trauma care in the AOR. Trauma care in PACOM is often deferred to civilian facilities. RESULTS: Core elements of a Joint Theater Trauma System (JTTS) as established during combat operations in U.S. Central Command are applicable during Phase Zero. A PACOM JTTS was established to address the region's readiness to respond to Phase Zero trauma as well as escalation of regional threats. Information technology coordination was a critical hurdle to overcome. CONCLUSION: PACOM lessons learned are applicable to other Geographic Combatant Commands developing a JTTS during Phase Zero operations.
