title: D-amino acid based protein arginine deiminase inhibitors: Synthesis, pharmacokinetics, and in cellulo efficacy.
abstract: The protein arginine deiminases (PADs) are known to play a crucial role in the onset and progression of multiple inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and cancer. However, it is not known how each of the five PAD isozymes contributes to disease pathogenesis. As such, potent, selective, and bioavailable PAD inhibitors will be useful chemical probes to elucidate the specific roles of each isozyme. Since D-amino amino acids often possess enhanced in cellulo stability, and perhaps unique selectivities, we synthesized a series of D-amino acid analogs of our pan-PAD inhibitor Cl-amidine, hypothesizing that this change would provide inhibitors with enhanced pharmacokinetic properties. Herein, we demonstrate that d-Cl-amidine and d-o-F-amidine are potent and highly selective inhibitors of PAD1. The pharmacokinetic properties of d-Cl-amidine were moderately improved over those of l-Cl-amidine, and this compound exhibited similar cell killing in a PAD1 expressing, triple-negative MDA-MB-231 breast cancer cell line. These inhibitors represent an important step in our efforts to develop stable, bioavailable, and highly selective inhibitors for all of the PAD isozymes.
authors: Department of Chemistry, The Scripps Research Institute, Scripps Florida, 120 Scripps Way, Jupiter, FL 33458.
authors: Kevin L
authors: KL
authors: Bicker
authors: Lynne
authors: L
authors: Anguish
authors: Alexander A
authors: AA
authors: Chumanevich
authors: Michael D
authors: MD
authors: Cameron
authors: Xiangli
authors: X
authors: Cui
authors: Erin
authors: E
authors: Witalison
authors: Venkataraman
authors: V
authors: Subramanian
authors: Xuesen
authors: X
authors: Zhang
authors: Alena P
authors: AP
authors: Chumanevich
authors: Lorne J
authors: LJ
authors: Hofseth
authors: Scott A
authors: SA
authors: Coonrod
authors: Paul R
authors: PR
authors: Thompson
keywords: Cl-amidine; MDA-MB-231 Cells; PADs; Pharmacokinetics; d-Amino Acids