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Benzoxazolone carboxamides: potent and systemically active inhibitors of intracellular acid ceramidase.

Pizzirani D, Bach A, Realini N, Armirotti A, Mengatto L, Bauer I, Girotto S, Pagliuca C, De Vivo M, Summa M, Ribeiro A, Piomelli D - Angew. Chem. Int. Ed. Engl. (2014)

Bottom Line: Because of its central role in the ceramide metabolism, AC may offer a novel molecular target in disorders with dysfunctional ceramide-mediated signaling.Here, a class of benzoxazolone carboxamides is identified as the first potent and systemically active inhibitors of AC.Prototype members of this class inhibit AC with low nanomolar potency by covalent binding to the catalytic cysteine.

View Article: PubMed Central - PubMed

Affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova (Italy).

No MeSH data available.


In vivo profile of 17 a. Plasma pharmacokinetic profile of 17 a after i.p. (10 mg kg−1) and i.v. (1 mg kg−1) administration in mice (A). Identification of 19 as primary in vivo metabolite of 17 a: superimposed MRM traces of a standard sample of 17 a (retention time 3.91 min, 1 μm calibrator, red trace) and a sample collected 1 h after i.p. administration of 17 a in mice (10 mg kg−1; black trace) (B). The peak at 1.4 min corresponds to the primary metabolite of 17 a (19, 227 Da molecular mass, m/z: 228 detected in ESI mode). Effects of 17 a (10 mg kg−1, 3 h) on AC activity in mouse tissues (C) and sphingolipid levels in lungs (D). Values are expressed as means ±S.E.M (n=6).
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fig08: In vivo profile of 17 a. Plasma pharmacokinetic profile of 17 a after i.p. (10 mg kg−1) and i.v. (1 mg kg−1) administration in mice (A). Identification of 19 as primary in vivo metabolite of 17 a: superimposed MRM traces of a standard sample of 17 a (retention time 3.91 min, 1 μm calibrator, red trace) and a sample collected 1 h after i.p. administration of 17 a in mice (10 mg kg−1; black trace) (B). The peak at 1.4 min corresponds to the primary metabolite of 17 a (19, 227 Da molecular mass, m/z: 228 detected in ESI mode). Effects of 17 a (10 mg kg−1, 3 h) on AC activity in mouse tissues (C) and sphingolipid levels in lungs (D). Values are expressed as means ±S.E.M (n=6).

Mentions: Pharmacokinetic analyses showed that 17 a quickly enters the bloodstream after a single intraperitoneal (i.p. 10 mg kg−1) administration in mice (Figure 8 A), reaching a maximal plasma concentration, Cmax, of 1767.9 ng mL−1 and displaying a half-life time of 458 min in circulation. Relevant pharmacokinetic parameters are reported in Table S3 (Supporting Information). The primary in vivo metabolite of 17 a, the hydrolysis product 19 (Figure 8 B), did not inhibit AC in vitro at 10 μmμm.


Benzoxazolone carboxamides: potent and systemically active inhibitors of intracellular acid ceramidase.

Pizzirani D, Bach A, Realini N, Armirotti A, Mengatto L, Bauer I, Girotto S, Pagliuca C, De Vivo M, Summa M, Ribeiro A, Piomelli D - Angew. Chem. Int. Ed. Engl. (2014)

In vivo profile of 17 a. Plasma pharmacokinetic profile of 17 a after i.p. (10 mg kg−1) and i.v. (1 mg kg−1) administration in mice (A). Identification of 19 as primary in vivo metabolite of 17 a: superimposed MRM traces of a standard sample of 17 a (retention time 3.91 min, 1 μm calibrator, red trace) and a sample collected 1 h after i.p. administration of 17 a in mice (10 mg kg−1; black trace) (B). The peak at 1.4 min corresponds to the primary metabolite of 17 a (19, 227 Da molecular mass, m/z: 228 detected in ESI mode). Effects of 17 a (10 mg kg−1, 3 h) on AC activity in mouse tissues (C) and sphingolipid levels in lungs (D). Values are expressed as means ±S.E.M (n=6).
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Related In: Results  -  Collection

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fig08: In vivo profile of 17 a. Plasma pharmacokinetic profile of 17 a after i.p. (10 mg kg−1) and i.v. (1 mg kg−1) administration in mice (A). Identification of 19 as primary in vivo metabolite of 17 a: superimposed MRM traces of a standard sample of 17 a (retention time 3.91 min, 1 μm calibrator, red trace) and a sample collected 1 h after i.p. administration of 17 a in mice (10 mg kg−1; black trace) (B). The peak at 1.4 min corresponds to the primary metabolite of 17 a (19, 227 Da molecular mass, m/z: 228 detected in ESI mode). Effects of 17 a (10 mg kg−1, 3 h) on AC activity in mouse tissues (C) and sphingolipid levels in lungs (D). Values are expressed as means ±S.E.M (n=6).
Mentions: Pharmacokinetic analyses showed that 17 a quickly enters the bloodstream after a single intraperitoneal (i.p. 10 mg kg−1) administration in mice (Figure 8 A), reaching a maximal plasma concentration, Cmax, of 1767.9 ng mL−1 and displaying a half-life time of 458 min in circulation. Relevant pharmacokinetic parameters are reported in Table S3 (Supporting Information). The primary in vivo metabolite of 17 a, the hydrolysis product 19 (Figure 8 B), did not inhibit AC in vitro at 10 μmμm.

Bottom Line: Because of its central role in the ceramide metabolism, AC may offer a novel molecular target in disorders with dysfunctional ceramide-mediated signaling.Here, a class of benzoxazolone carboxamides is identified as the first potent and systemically active inhibitors of AC.Prototype members of this class inhibit AC with low nanomolar potency by covalent binding to the catalytic cysteine.

View Article: PubMed Central - PubMed

Affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova (Italy).

No MeSH data available.