BI 1015550 (PDE4 inhibitor) ✔️

Boehringer Ingelheim

Confirmed correct on March 29, 2023 at ACS Spring 2023 First Time Disclosures.

BI 1015550 is an oral phosphodiesterase 4 (PDE4) inhibitor developed by Boehringer Ingelheim that is currently in phase 3 for idiopathic pulmonary fibrosis (IPF; NCT05321069, NCT05321082). Amazingly, it’s been in the clinc circa 2012 but BI has yet to officially disclose the structure.

The phosphodiesterase family hydrolyzes cyclic AMP, which are second messengers in various signaling cascades. Inhibition of PDE4 has been explored for other inflammatory diseases, such as COPD and psoriasis/psoriatic arthritis, both of which have FDA-approved drugs (roflumilast, apremilast, respectively).

BI 1015550 is a preferential inhibitor of the PDE4B isoform being developed for IPF. In May 2022, the results of a phase 2 trial (NCT04419506) with BI 1015550 in IPF were published in NEJM, which showed that treatment with either BI 1015550 (18 mg BID) alone or in combination with other anti-fibrotic agents prevented a decrease in lung function, as determined by a change in forced vital capacity at 12 weeks.

Hiding in plain sight

This compound was remarkably easy to figure out, thanks to lessons that I’ve learned with GBT-601. That is, always check PubChem first!

When you search for BI 1015550 in PubChem…BOOM, you get a structure. Note R stereochemistry at S.

PubChem: an accessible & powerful datbase. It curates data from MULTIPLE government databases, including ones from the FDA, NIH subdivisions, etc. As many of you know, these clinical compounds have a crazy number of identifying codes assignened to them from. Sometimes you get lucky and PubChem conveniently sources them and places all synonyms here, including the unique ingredient identifier (UNII), which indicates the compound has been or is under clinical evaluation.

Interestingly, when I was first checking to see whether the structure of this compound had been published already, I came across this website that had correctly identified the structure from the patents! Ha! Love to see it.

Doublechecking

Indeed, the PubChem structure associated with BI 1015550 is Example 2 in WO 2013/026797, as noted by the Malaria Pharmacology website above.

While PubChem aggregates literature on BI 1015550, interestingly, the site itself does not state what the target or mechanism of action are. So, to check that this is the right compound, I looked further into the linked databases.

Looking through the NCATS GSRS, I noticed that this compound is an Orphan Drug. This means that it is listed in the FDA Orphan Drug Database. Cross-checking, BI did indeed announce that BI 1015550 had received Orphan Drug designation.

So, checking the Orphan Drug database, we indeed confirm that BI 1015550 is a PDE4B inhibitor.

So there we have it! Short and sweet :) Stay tuned for Wednesday’s post on Merck’s PCSK9i—a 2 for 1 special this week before ACS Spring 2023.

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