Bayer HealthCare Tests Chemical Libraries for New PAH Treatment

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Research scientists at Bayer HealthCare AG in Germany are optimizing a new chemical inhibitor for pulmonary arterial hypertension (PAH) treatment. The team of medicinal chemists generated a library of compounds centered around inhibiting human neutrophil elastase (HNE), a key driver of inflammation in PAH. After generating molecules that successfully inhibited HNE, the team treated rats with monocrotaline-induced PAH and found an attenuation of symptoms.

“Human neutrophil elastase (HNE) is a key driver of inflammation in many cardiopulmonary and systemic inflammatory and autoimmune conditions,” wrote Dr. F. von Nussbaum, lead author in the Medicinal Chemistry Department in Berlin at Bayer HealthCare AG. “Overshooting high HNE activity is the consequence of a disrupted protease-antiprotease balance.” Since HNE appears to drive PAH disease onset and progression, inhibiting HNE may be a feasible PAH treatment option.

Prior to this study, Bayer HealthCare already knew of two potential candidates for HNE inhibition. The research team previously worked with chemical probe BAY-678 and the clinical candidate BAY 85-8501. In general, although compounds may show some level of inhibition, often times they can be improved in terms of efficacy or stability in the body. The team sought to do this for their current hits.

Pharmaceutical companies generate libraries of compounds that are based around a parent molecule. In this case, the research team began with ring topologies along the equator of the parent lead molecule. They incorporated functional groups ranging from imidazolo- and tetrazolopyrimidines in an effort to make the resultant molecules “fit” better into the inhibitory pocket of HNE. All the molecules generated were described in the researchers’ article, “Potent and Selective Human Neutrophil Elastase Inhibitors with Novel Equatorial Ring Topology: in vivo Efficacy of the Polar Pyrimidopyridazine BAY-8040 in a Pulmonary Arterial Hypertension Rat Model,” which was published in ChemMedChem.


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Modifying the west side of the molecule yielded a particularly potent and selective inhibitor of HNE. The researchers then orally administered the molecule, BAY-8040, to rats with induced PAH and saw a positive response. With this proof of concept available in rats, more extensive research may be conducted for BAY-8040 to bring it into Phase 1 clinical trials in humans.

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Maureen Newman is a science columnist for Pulmonary Hypertension News. She is currently a PhD student studying biomedical engineering at University of Rochester, working towards a career of research in biomaterials for drug delivery and regenerative medicine. She is an integral part of Dr. Danielle Benoit's laboratory, where she is investigating bone-homing therapeutics for osteoporosis treatment.
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