The Bradykinin B1 receptor is rapidly induced upon tissue injury and inflammation, stimulating the production of inflammatory mediators resulting in plasma extravasation, leukocyte trafficking, edema, and pain. B1 receptor expression is enhanced in the synovial tissue of patients with osteoarthritis and rheumatoid arthritis. We have previously reported on sulfonamide and sulfone based B1 antagonists containing a privileged bicyclic amine moiety leading to the potent oxopiperazine AMG 327.  The suboptimal PK and physicochemical properties of the oxopiperazines led us to seek B1 antagonists with improved drug-like properties.  Using a pharmacophore model containing the bicyclic amine as anchor, we designed a series of amide antagonists with restrictions on polar surface area, molecular weight and the number of hydrogen bond donors.  This approach led to a novel series of potent phthalazinone B1 antagonists.  SAR studies revealed compounds with sub-nM B1 affinity.  These compounds demonstrate excellent PK properties in rats with oral bioavailability in the 60-90% range.  SAR, PK and rabbit in vivo efficacy studies in a biochemical challenge model and a carrageenan-induced mechanical hyperalgesia model with the phthalazinones will be discussed.

Discovery of potent and orally bioavailable phthalazinone Bradykinin B1 receptor antagonists for chronic pain

240th National Meeting (2010)

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