Potent and Selective Nonpeptidic Inhibitors of Procollagen C-Proteinase

• Published in: Journal of medicinal chemistry 2007-07, Vol.50 (15), p.3442-3456
• Main Authors: Fish, Paul V, Allan, Gillian A, Bailey, Simon, Blagg, Julian, Butt, Richard, Collis, Michael G, Greiling, Doris, James, Kim, Kendall, Jackie, McElroy, Andrew, McCleverty, Dawn, Reed, Charlotte, Webster, Robert, Whitlock, Gavin A
• Format: Article
• Language: English
• Subjects: Administration, Cutaneous; Biological and medical sciences; Bone Morphogenetic Protein 1; Bone Morphogenetic Proteins - antagonists & inhibitors; Cicatrix, Hypertrophic - prevention & control; Collagen - metabolism; Dermatologic Agents - chemical synthesis; Dermatologic Agents - pharmacokinetics; Dermatologic Agents - pharmacology; Fibroblasts - cytology; Fibroblasts - drug effects; Humans; Hydrolysis; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; In Vitro Techniques; Keloid - prevention & control; Matrix Metalloproteinase Inhibitors; Medical sciences; Metalloendopeptidases - antagonists & inhibitors; Oxadiazoles - chemical synthesis; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Permeability; Pharmacology. Drug treatments; Skin - cytology; Skin - drug effects; Skin - metabolism; Skin, nail, hair, dermoskeleton; Solubility; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061010z

6-Cyclohexyl-N-hydroxy-3-(1,2,4-oxadiazol-5-yl)hexanamides were previously disclosed as inhibitors of procollagen C-proteinase (PCP) culminating in the identification of amide 1. Our objective was to discover a second inhibitor that would have improved affinity for PCP and to optimize properties for transepidermal delivery (TED) to intact skin. Further investigation of this template identified a number of potent PCP inhibitors (IC50 values of 2−6 nM) with improved TED flux. Sulfonamide 56 had excellent PCP enzyme activity when measured with a peptide substrate (K i 8.7 nM) or with the endogenous substrate procollagen (IC50 3.4 nM) and demonstrates excellent selectivity over MMPs involved in wound healing (>10 000-fold). In the fibroplasia model, 56 inhibited deposition of insoluble collagen by 76 ± 2% at 10 μM and was very effective at penetrating human skin in vitro with a TED flux of 1.5 μg/cm2/h, which compares favorably with values for agents that are known to penetrate skin well in vivo. Based on this profile, 56 (UK-421,045) was selected as a candidate for further preclinical evaluation as a topically applied, dermal anti-scarring agent.