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Synthesis of Brensocatib (BRINSUPRI)

astinovabiolabs · · 4 min read

Compiled: 2026-06-16 · Trigger event: FDA approval, 2025-08-12 Innovator: Insmed Incorporated (originator AstraZeneca; AZD7986, worldwide-licensed to Insmed Oct 2016 as INS1007) Status: Approved NME

INN: brensocatibBrand (US): BRINSUPRICAS: 1802148-05-5ChEMBL: CHEMBL3900409MW: 420.5 g/molNDA #: NDA 217673Approval: 2025-08-12

Mechanism: Brensocatib is a competitive, reversible (reversible-covalent, via a nitrile warhead engaging the catalytic Cys) inhibitor of dipeptidyl peptidase 1 (DPP1, cathepsin C; ChEMBL target CHEMBL2252). DPP1 activates pro-inflammatory neutrophil serine proteases (NSPs) — neutrophil elastase, cathepsin G, proteinase 3 — during neutrophil maturation in the bone marrow. By blocking DPP1, brensocatib lowers the activity of mature-neutrophil NSPs that drive the airway-damage cycle of neutrophil-mediated NCFB inflammation. Refs: PMID 27690432 (discovery), PMID 29484635.

Synthesis Route of the Originator

Convergent synthesis disclosed in the AstraZeneca discovery paper (Doyle et al., J. Med. Chem. 2016, 59, 9457-9472; AZD7986 = compound 30). The eastern warhead precursor is built from 4-bromo-L-phenylalaninamide (N-Boc): Suzuki–Miyaura coupling with 3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-ylboronate (SM-2) forms the biaryl (INT-2). Boc removal (INT-3), then amide coupling with N-Boc-(2S)-1,4-oxazepane-2-carboxylic acid (SM-3) builds the central amide (INT-4, the penultimate bis-amide). The terminal primary amide is then dehydrated (Burgess reagent, or TFAA/Et₃N, cold) to the reversible-covalent nitrile warhead (INT-5); final Boc removal and crystallisation from aqueous ethanol give brensocatib monohydrate. The amide→nitrile dehydration is intentionally the last C-modifying step to avoid epimerising the (1S) alpha-amino-nitrile centre. Both stereocentres are (S): the warhead centre derives from L-phenylalanine and the oxazepane is the (2S) building block. Conditions are representative for the named transformations — verify against originator/process literature before scale-up.

aReagents and conditions: (1) 3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-ylboronic acid pinacol ester (1.1 eq), Pd(dppf)Cl₂ (3–5 mol%), K₃PO₄ or K₂CO₃ (2–3 eq), 1,4-dioxane/H₂O 4:1, 80–90 °C, 4–12 h; (2) HCl (4 M in 1,4-dioxane) or TFA/CH₂Cl₂, rt, 1–2 h; free-base on workup; (3) N-Boc-(2S)-1,4-oxazepane-2-carboxylic acid (1.05 eq), T3P (1.5 eq) or HATU (1.2 eq), DIPEA (2–3 eq), DMF or EtOAc, 0 °C → rt, 2–6 h; (4) Burgess reagent (1.3 eq), THF, 40–60 °C; or TFAA (1.2 eq)/Et₃N, CH₂Cl₂, −10 °C → 0 °C. Mild, low-temperature dehydration selective for the 1° amide; preserves the (1S) alpha-amino-nitrile stereocentre; (5) HCl/dioxane or TFA/CH₂Cl₂, rt; free-base, then crystallise from aqueous EtOH to give brensocatib monohydrate (drug-substance form, C₂₃H₂₄N₄O₄·H₂O, MW 438.48).

Key intermediates

Key patent filings

atent / ApplicationTypeAssigneeFiledExpiry (~)
AstraZeneca composition-of-matter family — oxazepane amidoacetonitrile DPP1 series [VERIFY exact WO/US no. on Espacenet]Composition of matter (originator)AstraZeneca ABPriority ~2014–2015 (the 2nd-generation reversible-covalent DPP1 inhibitor series described in Doyle et al., J. Med. Chem. 2016)~2034–2036 nominal (20 yr from filing), before any PTE
Insmed-era patents — ‘Reversible DPP1 inhibitors and uses thereof’ / formulation & method-of-use [VERIFY exact nos.]Formulation / method-of-use / polymorphInsmed Incorporated~2019–2024~2039–2044 nominal
Process patent(s) — building-block routesProcessAstraZeneca / Insmed / CDMO [VERIFY]~2015–2022~2035–2042

Approved indication

  • Approval date (US): 2025-08-12
  • NDA number: NDA 217673
  • Brand (US): BRINSUPRI
  • Indication: Treatment of non-cystic fibrosis bronchiectasis (NCFB) in adult and pediatric patients 12 years of age and older. First-in-class: the first DPP1 (dipeptidyl peptidase 1) inhibitor and the first drug ever approved specifically for bronchiectasis.
  • Dosage form / strength: Film-coated tablet, oral. 10 mg (brown, round, debossed ’10’/’BRE’); 25 mg (gray, round, debossed ’25’/’BRE’)
  • Review pathway: NDA, Type 1 New Molecular Entity, Priority Review; approval letter dated 2025-08-13 (per openFDA). Breakthrough Therapy Designation granted for NCFB.

Crystal Forms, Salts, and Solid-State Profile

  • API in approved drug product: Brensocatib monohydrate (C₂₃H₂₄N₄O₄·H₂O, MW 438.48; free base 420.47). White to off-white solid powder. Slightly soluble at pH 1.2, freely soluble at pH 4.5, very slightly soluble at pH 6.8; soluble in MeCN, sparingly soluble in EtOH.
  • Strengths approved: 10 mg and 25 mg oral film-coated tablets, QD
  • Third-party polymorph activity: No third-party US polymorph activity identified as of 2026-06-16 — expected given the long-dated COM. Monitor SureChEMBL/Espacenet.
  • Originator polymorph filing: Insmed monohydrate drug-substance form is the marketed solid form; polymorph/hydrate claims expected within the Insmed estate

Key peer-reviewed literature