title: Transdermal pharmacology of small molecule cyclic C5a antagonists.
abstract: Overproduction or underregulation of the proinflammatory complement component C5a has been implicated in numerous immune and inflammatory conditions. Therefore, targeting the C5a receptor (C5aR) has become an innovative strategy for antiinflammatory drug development. The novel cyclic peptide C5aR antagonist, AcF-[OP(D-Cha)WR] (PMX53), attenuates injury in numerous animal models of inflammation following intravenous, subcutaneous, intraperitoneal, and oral administration. In the present study the transdermal pharmacology of PMX53 and three analogs designed with increased lipophilicity, hydrocinnamate-[OP(D-Cha)WCit] (PMX200), AcF-[OP(D-Cha)WCit] (PMX201) and hydrocinnamate-[OP(D-Cha)WR] (PMX205), have been examined in order to assess their transdermal permeability and inhibitory effect on C5a-mediated lipopolysaccharide (LPS)-induced systemic responses. In the rat, PMX53, PMX201, and PMX205, were bioavailable following topical dermal administration (10 mg/50 cm2 site/rat). All analogs functionally antagonized neutropenia and hypotension induced by systemic challenge with LPS (1 mg/kg i.v.). Interestingly, PMX200 attenuated LPS-induced neutropenia more effectively than other analogs, despite undetectable (<5 ng/ml) circulating levels following topical administration. In conclusion, we have demonstrated that cyclic peptide C5aR antagonists can penetrate transdermally sufficiently to have systemic effects. However, increasing lipophilicity in these compounds did not result in increased blood levels. Nonetheless, topical application of C5aR antagonists produced circulating levels of the drugs that antagonized the LPS-induced systemic responses of neutropenia and hypotension. This suggests that these small-molecule C5aR antagonists may be developed for topical administration for the treatment of local and systemic inflammatory conditions in the human and veterinary pharmaceutical markets.
authors.affiliation: Promics Ltd., Australia.
authors.forename: Lavinia M
authors.initials: LM
authors.lastname: Proctor
authors.forename: Trent M
authors.initials: TM
authors.lastname: Woodruff
authors.forename: Prakirti
authors.initials: P
authors.lastname: Sharma
authors.forename: Ian A
authors.initials: IA
authors.lastname: Shiels
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Taylor
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D015936:Complement C5a / Q000276:immunology*; D003169:Complement Inactivator Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D005260:Female; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D007155:Immunologic Factors / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology / Q000633:toxicity; D015394:Molecular Structure; D009503:Neutropenia / Q000139:chemically induced; D009504:Neutrophils / Q000378:metabolism; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D003169:Complement Inactivator Proteins; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a