1,4-Oxazepanes for Drug Discovery
The 1,4-oxazepane is increasingly showing what a seven-membered saturated heterocycle can offer in medicinal chemistry. As a ring-expanded homologue of morpholine, it retains the ether oxygen and basic nitrogen while adding a single methylene, which alters ring conformation, exit vectors and the spacing between the two heteroatoms. In programmes where a morpholine or piperazine sits close to the desired profile, the oxazepane can offer a valuable additional handle on shape, basicity and physicochemical properties. That potential was validated in August 2025, when the FDA approved brensocatib \(Brinsupri\), developed by Insmed under licence from AstraZeneca, as the first treatment for non-cystic fibrosis bronchiectasis and the first approved inhibitor of dipeptidyl peptidase 1 \(DPP1\). At its core sits a \(2S\)-1,4-oxazepane-2-carboxamide. AstraZeneca's discovery campaign described a second-generation series of reversible covalent DPP1 inhibitors with an improved off-target profile, culminating in the oxazepane amidoacetonitrile clinical candidate AZD7986. In the phase 3 ASPEN trial of more than 1,700 patients, both doses reduced the annualised rate of pulmonary exacerbations by around 20% relative to placebo, and brensocatib went on to receive a positive opinion in the EU in October 2025. Among approved drugs, the ring and its benzo-fused 1,4-oxazepine relatives now feature in at least three therapeutic areas: respiratory medicine with brensocatib, oncology with the PI3Kα inhibitor inavolisib, and psychiatry with the antipsychotic loxapine. Beyond the clinic, oxazepane chemotypes are attracting interest as sp³-rich, three-dimensional scaffolds for library design, and with DPP1 now a clinically validated target, this motif looks well placed to draw growing attention from medicinal chemists in the years ahead. Explore our range of building blocks using the advanced search tools at https://lnkd.in/eVbfw6Ua To read more take a look at the following papers: 1. Brensocatib: First Approval https://lnkd.in/ebq8j2r5 2. Dipeptidyl peptidase 1 inhibitors for inflammatory respiratory diseases: mechanisms, clinical trials, and therapeutic prospects https://lnkd.in/eN36N5EX 3. Short Scalable Route to Bis-morpholine Spiroacetals and Oxazepane Analogues: Useful 3D-Scaffolds for Compound Library Assembly https://lnkd.in/eggZNn9V