Discovery of JNJ-74856665: A Novel Isoquinolinone DHODH Inhibitor for the Treatment of AML.

Acute myelogenous leukemia (AML), a heterogeneous disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway and preclinical findings demonstrated that DHODH is a metabolic vulnerability in AML as inhibitors can induce differentiation across multiple AML subtypes. As a result of virtual screening and structure-based drug design approaches, a novel series of isoquinolinone DHODH inhibitors was identified. Further lead optimization afforded JNJ-74856665 as an orally bioavailable, potent, and selective DHODH inhibitor with favorable physicochemical properties selected for clinical development in patients with AML and myelodysplastic syndromes (MDS).

N-Heterocyclic 3-Pyridyl Carboxamide Inhibitors of DHODH for the Treatment of Acute Myelogenous Leukemia.

Acute myelogenous leukemia (AML), a disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway; however, small molecule DHODH inhibitors were recently shown to induce differentiation in multiple AML subtypes. Using virtual screening and structure-based drug design approaches, a new series of N-heterocyclic 3-pyridyl carboxamide DHODH inhibitors were discovered. Two lead compounds, 19 and 29, have potent biochemical and cellular DHODH activity, favorable physicochemical properties, and efficacy in a preclinical model of AML.

Benefit of mechanical chest compression devices in mountain HEMS: lessons learned from 1 year of experience and evaluation.

INTRODUCTION: Pre-hospital care of cardiac arrest patients in the mountain environment is one of the most challenging problems for helicopter medical emergency services (HEMS) teams. To provide high-quality chest compression with minimal hand s-off-time is very demanding in the alpine area. METHODS: We used and evaluated mechanical chest compression devices (Lucas and AutoPulse) and investigated if these are good and useful tools in the alpine HEMS. Over a period of 12 months we performed 7 CPRs in remote alpine terrain. CONCLUSION: On the strength of our past experience, CPR under special circumstances like deep hypothermia, in which a prolonged CPR is essential, the use of the Lucas and/or AutoPulse was an easy and sufficient tool even in difficult alpine terrain which requires special rescue missions like winch or MERS evacuation.

Mechanical chest compressions in an avalanche victim with cardiac arrest: an option for extreme mountain rescue operations.

Mountain rescue operations often present helicopter emergency medical service crews with unique challenges. One of the most challenging problems is the prehospital care of cardiac arrest patients during evacuation and transport. In this paper we outline a case in which we successfully performed a cardiopulmonary resuscitation of an avalanche victim. A mechanical chest-compression device proved to be a good way of minimizing hands-off time and providing high-quality chest compressions while the patient was evacuated from the site of the accident.