title: Potent and selective nonpeptidic inhibitors of procollagen C-proteinase.
abstract: 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 (Ki 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 microM and was very effective at penetrating human skin in vitro with a TED flux of 1.5 microg/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.
authors.affiliation: Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ, United Kingdom. paul.fish@pfizer.com
authors.forename: Paul V
authors.initials: PV
authors.lastname: Fish
authors.forename: Gillian A
authors.initials: GA
authors.lastname: Allan
authors.forename: Simon
authors.initials: S
authors.lastname: Bailey
authors.forename: Julian
authors.initials: J
authors.lastname: Blagg
authors.forename: Richard
authors.initials: R
authors.lastname: Butt
authors.forename: Michael G
authors.initials: MG
authors.lastname: Collis
authors.forename: Doris
authors.initials: D
authors.lastname: Greiling
authors.forename: Kim
authors.initials: K
authors.lastname: James
authors.forename: Jackie
authors.initials: J
authors.lastname: Kendall
authors.forename: Andrew
authors.initials: A
authors.lastname: McElroy
authors.forename: Dawn
authors.initials: D
authors.lastname: McCleverty
authors.forename: Charlotte
authors.initials: C
authors.lastname: Reed
authors.forename: Robert
authors.initials: R
authors.lastname: Webster
authors.forename: Gavin A
authors.initials: GA
authors.lastname: Whitlock
mesh_terms: D000279:Administration, Cutaneous; D055395:Bone Morphogenetic Protein 1; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors*; D017439:Cicatrix, Hypertrophic / Q000517:prevention & control; D003094:Collagen / Q000378:metabolism; D003879:Dermatologic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007627:Keloid / Q000517:prevention & control; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010539:Permeability; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C523406:6-cyclohexyl-N-hydroxy-3-(3-(((methylsulfonyl)amino)methyl)-1,2,4-oxadiazol-5-yl)hexanamide; D019485:Bone Morphogenetic Proteins; D003879:Dermatologic Agents; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D010069:Oxadiazoles; D003094:Collagen; D008666:Metalloendopeptidases; C525705:BMP1 protein, human; D055395:Bone Morphogenetic Protein 1