Biochemical and pharmacological characterization of FK706, a novel elastase inhibitor

Biochemical and Pharmacological Characterization of 2-(9-(2-Piperidinoethoxy)-4-oxo-4 H-pyrido[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-methylethyl)-6-methoxy-1,2-benzisothiazol-3(2 H)-one-1,1-dioxide (SSR69071), a Novel, Orally Active Elastase Inhibitor

“…Human neutrophil elastase also elicited paw edema as did other irritants such as zymosan, carrageenan, and bradykinin. The paw edema in this model is thought to reflect increases in permeability of the peripheral capillaries (Shinguh et al, 1997). Nakagawa et al (1986) showed that a selective elastase inhibitor attenuated the vascular permeability increase, leukocyte cell migration, and development of granulated tissue induced by carrageenan.…”

“…SSR69071 is more effective than FK706 (Shinguh et al, 1997), ONO-5046 (Kawabata et al, 1991), and GW-311616A (Norman, 1998), according to the K i values. SSR69071 has a fast association rate and slow dissociation rate, resulting in a stable, slowly reversible HLE-inhibitor complex.…”

“…Shinguh et al (1997) showed that selective elastase inhibitors could prevent edema formation induced by elastase in an experimental model in mice. Human neutrophil elastase also elicited paw edema as did other irritants such as zymosan, carrageenan, and bradykinin.…”

Inhibition of elastase-induced acute inflammation and pulmonary emphysema in hamsters by a novel neutrophil elastase inhibitor FR901277

“…48, 1999 Elastase inhibition by FR901277 inhibited all of serine proteinases we studied, including trypsin, with almost similar potency under our assay conditions. There have been some reports of other inhibitors of elastase; ICI220,880 [22] and SC39026 [23] are neutrophil elastase specific inhibitors, while MR889 [24], ONO5046 [25] and FK706 [21] are specific for both neutrophil and pancreatic elastase. FR901277 has unique characteristics different from those inhibitors and a1-PI, since it is relatively specific for elastases but inhibits chymotrypsin-type serine proteinases broadly.…”

“…The ability of FR901277 to prevent human elastase-induced lung hemorrhage was evaluated according to the method by Shinguh et al [21]. Briefly, female golden hamsters (approximately 80 g body weight) were anesthetized by intraperitoneal injection of 40 mg/kg of pentobarbital.…”