Discovery of TD-0212, an Orally Active Dual Pharmacology AT 1 Antagonist and Neprilysin Inhibitor (ARNI).

Autor: McKinnell RM; Theravance Biopharma US Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States., Fatheree P; Theravance Biopharma US Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States., Choi SK; Theravance Biopharma US Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States., Gendron R; Theravance Biopharma US Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States., Jendza K; Theravance Biopharma US Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States., Olson Blair B; Theravance Biopharma US Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States., Budman J; Theravance Biopharma US Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States., Hill CM; Theravance Biopharma US Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States., Hegde LG; Theravance Biopharma US Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States., Yu C; Theravance Biopharma US Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States., McConn D; Theravance Biopharma US Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States., Hegde SS; Theravance Biopharma US Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States., Marquess DG; Theravance Biopharma US Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States., Klein U; Theravance Biopharma US Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2018 Dec 03; Vol. 10 (1), pp. 86-91. Date of Electronic Publication: 2018 Dec 03 (Print Publication: 2019).
DOI: 10.1021/acsmedchemlett.8b00462
Abstrakt: Dual inhibition of angiotensin-converting enzyme (ACE) and neprilysin (NEP) by drugs such as omapatrilat produces superior antihypertensive efficacy relative to ACE inhibitors but is associated with a higher risk of life-threatening angioedema due to bradykinin elevations. We hypothesized that dual AT 1 (angiotensin II type 1 receptor) blockade and NEP inhibition with a single molecule would produce similar antihypertensive efficacy to omapatrilat without the risk of angioedema since ACE (the rate limiting enzyme in bradykinin metabolism) would remain uninhibited. Merging the structures of losartan (an AT 1 antagonist) and thiorphan (a NEP inhibitor) led to the discovery of a novel series of orally active, dual AT 1 antagonist/NEP inhibitors (ARNIs) exemplified by compound 35 (TD-0212). In models of renin-dependent and -independent hypertension, 35 produced blood pressure reductions similar to omapatrilat and combinations of AT 1 receptor antagonists and NEP inhibitors. Upper airway angioedema risk was assessed in a rat tracheal plasma extravasation (TPE) model. Unlike omapatrilat, 35 did not increase TPE at antihypertensive doses. Compound 35 therefore provides the enhanced activity of dual AT 1 /NEP inhibition with a potentially lower risk of angioedema relative to dual ACE/NEP inhibition.
Competing Interests: The authors declare no competing financial interest.
Databáze: MEDLINE
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