Protease activated receptor 2 (PAR2) modulators: a patent review (2010–2015)

References

• Macfarlane SR, Seatter MJ, Kanke T, et al. Proteinase-activated receptors. Pharmacol Rev. 2001;53(2):245–282.
   PubMed Web of Science ®Google Scholar
• Adams MN, Ramachandran R, Yau MK, et al. Structure, function and pathophysiology of protease activated receptors. Pharmacol Ther. 2011;130(3):248–282.
   PubMed Web of Science ®Google Scholar
• Ramachandran R, Noorbakhsh F, Defea K, et al. Targeting proteinase-activated receptors: therapeutic potential and challenges. Nat Rev Drug Discov. 2012;11(1):69–86.
   PubMed Web of Science ®Google Scholar
• Nieman MT, Schmaier AH. Interaction of thrombin with PAR1 and PAR4 at the thrombin cleavage site. Biochemistry. 2007;46(29):8603–8610.
   PubMed Web of Science ®Google Scholar
• Yau MK, Liu L, Fairlie DP. Toward drugs for protease-activated receptor 2 (PAR2). J Med Chem. 2013;56(19):7477–7497.
   PubMed Web of Science ®Google Scholar
• Ramachandran R, Mihara K, Mathur M, et al. Agonist-biased signaling via proteinase activated receptor-2: differential activation of calcium and mitogen-activated protein kinase pathways. Mol Pharmacol. 2009;76(4):791–801.
   PubMed Web of Science ®Google Scholar
• Ramachandran R, Mihara K, Chung H, et al. Neutrophil elastase acts as a biased agonist for proteinase-activated receptor-2 (PAR2). J Biol Chem. 2011;286(28):24638–24648.
   PubMed Web of Science ®Google Scholar
• Elmariah SB, Reddy VB, Lerner EA. Cathepsin S signals via PAR2 and generates a novel tethered ligand receptor agonist. PLoS One. 2014;9(6):e99702.
   PubMed Web of Science ®Google Scholar
• Zhao P, Lieu T, Barlow N, et al. Cathepsin S causes inflammatory pain via biased agonism of PAR2 and TRPV4. J Biol Chem. 2014;289(39):27215–27234.
   PubMed Web of Science ®Google Scholar
• Hollenberg MD, Mihara K, Polley D, et al. Biased signalling and proteinase-activated receptors (PARs): targeting inflammatory disease. Br J Pharmacol. 2014;171(5):1180–1194.
   PubMed Web of Science ®Google Scholar
• Zhao P, Metcalf M, Bunnett NW. Biased signaling of protease-activated receptors. Front Endocrinol (Lausanne). 2014;5:67.
   PubMed Web of Science ®Google Scholar
• Katritch V, Cherezov V, Stevens RC. Structure-function of the G protein-coupled receptor superfamily. Annu Rev Pharmacol Toxicol. 2013;53:531–556.
   PubMed Web of Science ®Google Scholar
• Ghosh E, Kumari P, Jaiman D, et al. Methodological advances: the unsung heroes of the GPCR structural revolution. Nat Rev Mol Cell Biol. 2015;16(2):69–81.
   PubMed Web of Science ®Google Scholar
• Kimple AJ, Bosch DE, Giguere PM, et al. Regulators of G-protein signaling and their Gα substrates: promises and challenges in their use as drug discovery targets. Pharmacol Rev. 2011;63(3):728–749.
   PubMed Web of Science ®Google Scholar
• Suen JY, Cotterell A, Lohman RJ, et al. Pathway-selective antagonism of proteinase activated receptor 2. Br J Pharmacol. 2014;171(17):4112–4124.
   PubMed Web of Science ®Google Scholar
• Dutra-Oliveira A, Monteiro RQ, Mariano-Oliveira A. Protease-activated receptor-2 (PAR2) mediates VEGF production through the ERK1/2 pathway in human glioblastoma cell lines. Biochem Biophys Res Commun. 2012;421(2):221–227.
   PubMed Web of Science ®Google Scholar
• Guo D, Zhou H, Wu Y, et al. Involvement of ERK1/2/NF-kappaB signal transduction pathway in TF/FVIIa/PAR2-induced proliferation and migration of colon cancer cell SW620. Tumour Biol. 2011;32(5):921–930.
   PubMed Web of Science ®Google Scholar
• Coughlin SR, Camerer E. PARticipation in inflammation. J Clin Invest. 2003;111(1):25–27.
   PubMed Web of Science ®Google Scholar
• Steinhoff M, Buddenkotte J, Shpacovitch V, et al. Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response. Endocr Rev. 2005;26(1):1–43.
   PubMed Web of Science ®Google Scholar
• Barry GD, Le GT, Fairlie DP. Agonists and antagonists of protease activated receptors (PARs). Curr Med Chem. 2006;13(3):243–265.
   PubMed Web of Science ®Google Scholar
• Rothmeier AS, Ruf W. Protease-activated receptor 2 signaling in inflammation. Semin Immunopathol. 2012;34(1):133–149.
   PubMed Web of Science ®Google Scholar
• Colognato R, Slupsky JR, Jendrach M, et al. Differential expression and regulation of protease-activated receptors in human peripheral monocytes and monocyte-derived antigen-presenting cells. Blood. 2003;102(7):2645–2652.
   PubMed Web of Science ®Google Scholar
• Johansson U, Lawson C, Dabare M, et al. Human peripheral blood monocytes express protease receptor-2 and respond to receptor activation by production of IL-6, IL-8, and IL-1{beta}. J Leukoc Biol. 2005;78(4):967–975.
   PubMed Web of Science ®Google Scholar
• Steven R, Crilly A, Lockhart JC, et al. Proteinase-activated receptor-2 modulates human macrophage differentiation and effector function. Innate Immun. 2013;19(6):663–672.
   PubMed Web of Science ®Google Scholar
• Nikolakopoulou AM, Dutta R, Chen Z, et al. Activated microglia enhance neurogenesis via trypsinogen secretion. Proc Natl Acad Sci USA. 2013;110(21):8714–8719.
   PubMed Web of Science ®Google Scholar
• Rohatgi T, Henrich-Noack P, Sedehizade F, et al. Transient focal ischemia in rat brain differentially regulates mRNA expression of protease-activated receptors 1 to 4. J Neurosci Res. 2004;75(2):273–279.
   PubMed Web of Science ®Google Scholar
• Afkhami-Goli A, Noorbakhsh F, Keller AJ, et al. Proteinase-activated receptor-2 exerts protective and pathogenic cell type-specific effects in Alzheimer’s disease. J Immunol. 2007;179(8):5493–5503.
   PubMed Web of Science ®Google Scholar
• Jin G, Hayashi T, Kawagoe J, et al. Deficiency of PAR-2 gene increases acute focal ischemic brain injury. J Cereb Blood Flow Metab. 2005;25(3):302–313.
   PubMed Web of Science ®Google Scholar
• Noorbakhsh F, Vergnolle N, McArthur JC, et al. Proteinase-activated receptor-2 induction by neuroinflammation prevents neuronal death during HIV infection. J Immunol. 2005;174(11):7320–7329.
   PubMed Web of Science ®Google Scholar
• Kawabata A, Matsunami M, Sekiguchi F. Gastrointestinal roles for proteinase-activated receptors in health and disease. Br J Pharmacol. 2008;153(Suppl. 1):S230–S240.
   PubMed Web of Science ®Google Scholar
• Namkung W, Han W, Luo X, et al. Protease-activated receptor 2 exerts local protection and mediates some systemic complications in acute pancreatitis. Gastroenterology. 2004;126(7):1844–1859.
   PubMed Web of Science ®Google Scholar
• Sharma A, Tao X, Gopal A, et al. Protection against acute pancreatitis by activation of protease-activated receptor-2. Am J Physiol Gastrointest Liver Physiol. 2005;288(2):G388–G395.
   PubMed Web of Science ®Google Scholar
• Singh VP, Bhagat L, Navina S, et al. Protease-activated receptor-2 protects against pancreatitis by stimulating exocrine secretion. Gut. 2007;56(7):958–964.
   PubMed Web of Science ®Google Scholar
• Vergnolle N. Protease-activated receptors and inflammatory hyperalgesia. Mem Inst Oswaldo Cruz. 2005;100(Suppl. 1):173–176.
   PubMed Web of Science ®Google Scholar
• Lam FF. Role of protease-activated receptor 2 in joint inflammation. Arthritis Rheum. 2007;56(11):3514–3517.
   PubMed Web of Science ®Google Scholar
• Cenac N, Coelho AM, Nguyen C, et al. Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2. Am J Pathol. 2002;161(5):1903–1915.
   PubMed Web of Science ®Google Scholar
• Hansen KK, Sherman PM, Cellars L, et al. A major role for proteolytic activity and proteinase-activated receptor-2 in the pathogenesis of infectious colitis. Proc Natl Acad Sci USA. 2005;102(23):8363–8368.
   PubMed Web of Science ®Google Scholar
• McGuire JJ. Proteinase-activated receptor 2 (PAR2): a challenging new target for treatment of vascular diseases. Curr Pharm Des. 2004;10(22):2769–2778.
   PubMed Web of Science ®Google Scholar
• Weithauser A, Rauch U. Role of protease-activated receptors for the innate immune response of the heart. Trends Cardiovasc Med. 2014;24(6):249–255.
   PubMed Web of Science ®Google Scholar
• Cocks TM, Fong B, Chow JM, et al. A protective role for protease-activated receptors in the airways. Nature. 1999;398(6723):156–160.
   PubMed Web of Science ®Google Scholar
• Cocks TM, Moffatt JD. Protease-activated receptor-2 (PAR2) in the airways. Pulm Pharmacol Ther. 2001;14(3):183–191.
   PubMed Web of Science ®Google Scholar
• Liu C, Li Q, Zhou X, et al. Human airway trypsin-like protease induces mucin5AC hypersecretion via a protease-activated receptor 2-mediated pathway in human airway epithelial cells. Arch Biochem Biophys. 2013;535(2):234–240.
   PubMed Web of Science ®Google Scholar
• Regard JB, Kataoka H, Cano DA, et al. Probing cell type-specific functions of Gi in vivo identifies GPCR regulators of insulin secretion. J Clin Invest. 2007;117(12):4034–4043.
   PubMed Web of Science ®Google Scholar
• Badeanlou L, Furlan-Freguia C, Yang G, et al. Tissue factor-protease-activated receptor 2 signaling promotes diet-induced obesity and adipose inflammation. Nat Med. 2011;17(11):1490–1497.
   PubMed Web of Science ®Google Scholar
• Lim J, Iyer A, Liu L, et al. Diet-induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism. FASEB J. 2013;27(12):4757–4767.
   PubMed Web of Science ®Google Scholar
• Walker JK, DeFea KA. Role for β-arrestin in mediating paradoxical β2AR and PAR2 signaling in asthma. Curr Opin Pharmacol. 2014;16:142–147.
   PubMed Web of Science ®Google Scholar
• Schaffner F, Ruf W. Tissue factor and PAR2 signaling in the tumor microenvironment. Arterioscler Thromb Vasc Biol. 2009;29(12):1999–2004.
   PubMed Web of Science ®Google Scholar
• Su S, Li Y, Luo Y, et al. Proteinase-activated receptor 2 expression in breast cancer and its role in breast cancer cell migration. Oncogene. 2009;28(34):3047–3057.
   PubMed Web of Science ®Google Scholar
• Yang L, Ma Y, Han W, et al. Proteinase-activated receptor 2 promotes cancer cell migration through RNA methylation-mediated repression of miR-125b. J Biol Chem. 2015;290(44):26627–26637.
   PubMed Web of Science ®Google Scholar
• Amiable N, Martel-Pelletier J, Lussier B, et al. Proteinase-activated receptor-2 gene disruption limits the effect of osteoarthritis on cartilage in mice: a novel target in joint degradation. J Rheumatol. 2011;38(5):911–920.
   PubMed Web of Science ®Google Scholar
• Ferrell WR, Kelso EB, Lockhart JC, et al. Protease-activated receptor 2: a novel pathogenic pathway in a murine model of osteoarthritis. Ann Rheum Dis. 2010;69(11):2051–2054.
   PubMed Web of Science ®Google Scholar
• Xue M, Chan YK, Shen K, et al. Protease-activated receptor 2, rather than protease-activated receptor 1, contributes to the aggressive properties of synovial fibroblasts in rheumatoid arthritis. Arthritis Rheum. 2012;64(1):88–98.
   PubMed Web of Science ®Google Scholar
• Kawagoe J, Takizawa T, Matsumoto J, et al. Effect of protease-activated receptor-2 deficiency on allergic dermatitis in the mouse ear. Jpn J Pharmacol. 2002;88(1):77–84.
   PubMedGoogle Scholar
• Lohman RJ, Cotterell AJ, Barry GD, et al. An antagonist of human protease activated receptor-2 attenuates PAR2 signaling, macrophage activation, mast cell degranulation, and collagen-induced arthritis in rats. FASEB J. 2012;26(7):2877–2887.
   PubMed Web of Science ®Google Scholar
• Sevigny LM, Zhang P, Bohm A, et al. Interdicting protease-activated receptor-2-driven inflammation with cell-penetrating pepducins. Proc Natl Acad Sci USA. 2011;108(20):8491–8496.
   PubMed Web of Science ®Google Scholar
• Hyun E, Andrade-Gordon P, Steinhoff M, et al. Contribution of bone marrow-derived cells to the pro-inflammatory effects of protease-activated receptor-2 in colitis. Inflamm Res. 2010;59(9):699–709.
   PubMed Web of Science ®Google Scholar
• Iablokov V, Hirota CL, Peplowski MA, et al. Proteinase-activated receptor 2 (PAR2) decreases apoptosis in colonic epithelial cells. J Biol Chem. 2014;289(49):34366–34377.
   PubMed Web of Science ®Google Scholar
• Lohman RJ, Cotterell AJ, Suen J, et al. Antagonism of protease-activated receptor 2 protects against experimental colitis. J Pharmacol Exp Ther. 2012;340(2):256–265.
   PubMed Web of Science ®Google Scholar
• Schmidlin F, Amadesi S, Dabbagh K, et al. Protease-activated receptor 2 mediates eosinophil infiltration and hyperreactivity in allergic inflammation of the airway. J Immunol. 2002;169(9):5315–5321.
   PubMed Web of Science ®Google Scholar
• Page K, Ledford JR, Zhou P, et al. Mucosal sensitization to German cockroach involves protease-activated receptor-2. Respir Res. 2010;11:62.
   PubMed Web of Science ®Google Scholar
• de Boer JD, Van’t Veer C, Stroo I, et al. Protease-activated receptor-2 deficient mice have reduced house dust mite-evoked allergic lung inflammation. Innate Immun. 2014;20(6):618–625.
   PubMed Web of Science ®Google Scholar
• Lam DK, Dang D, Zhang J, et al. Novel animal models of acute and chronic cancer pain: a pivotal role for PAR2. J Neurosci. 2012;32(41):14178–14183.
   PubMed Web of Science ®Google Scholar
• Vergnolle N, Bunnett NW, Sharkey KA, et al. Proteinase-activated receptor-2 and hyperalgesia: a novel pain pathway. Nat Med. 2001;7(7):821–826.
   PubMed Web of Science ®Google Scholar
• Zhao P, Lieu T, Barlow N, et al. neutrophil elastase activates protease-activated receptor-2 (PAR2) and transient receptor potential vanilloid 4 (TRPV4) to cause inflammation and pain. J Biol Chem. 2015;290(22):13875–13887.
   PubMed Web of Science ®Google Scholar
• Liu S, Liu YP, Yue DM, et al. Protease-activated receptor 2 in dorsal root ganglion contributes to peripheral sensitization of bone cancer pain. Eur J Pain. 2014;18(3):326–337.
   PubMed Web of Science ®Google Scholar
• Kawabata A, Matsunami M, Tsutsumi M, et al. Suppression of pancreatitis-related allodynia/hyperalgesia by proteinase-activated receptor-2 in mice. Br J Pharmacol. 2006;148(1):54–60.
   PubMed Web of Science ®Google Scholar
• Joyal JS, Nim S, Zhu T, et al. Subcellular localization of coagulation factor II receptor-like 1 in neurons governs angiogenesis. Nat Med. 2014;20(10):1165–1173.
   PubMed Web of Science ®Google Scholar
• Versteeg HH, Schaffner F, Kerver M, et al. Protease-activated receptor (PAR) 2, but not PAR1, signaling promotes the development of mammary adenocarcinoma in polyoma middle T mice. Cancer Res. 2008;68(17):7219–7227.
   PubMed Web of Science ®Google Scholar
• Schaffner F, Versteeg HH, Schillert A, et al. Cooperation of tissue factor cytoplasmic domain and PAR2 signaling in breast cancer development. Blood. 2010;116(26):6106–6113.
   PubMed Web of Science ®Google Scholar
• Cicala C, Spina D, Keir SD, et al. Protective effect of a PAR2-activating peptide on histamine-induced bronchoconstriction in guinea-pig. Br J Pharmacol. 2001;132(6):1229–1234.
   PubMed Web of Science ®Google Scholar
• Cattaruzza F, Cenac N, Barocelli E, et al. Protective effect of proteinase-activated receptor 2 activation on motility impairment and tissue damage induced by intestinal ischemia/reperfusion in rodents. Am J Pathol. 2006;169(1):177–188.
   PubMed Web of Science ®Google Scholar
• Fiorucci S, Mencarelli A, Palazzetti B, et al. Proteinase-activated receptor 2 is an anti-inflammatory signal for colonic lamina propria lymphocytes in a mouse model of colitis. Proc Natl Acad Sci USA. 2001;98(24):13936–13941.
   PubMed Web of Science ®Google Scholar
• Borensztajn K, Stiekema J, Nijmeijer S, et al. Factor Xa stimulates proinflammatory and profibrotic responses in fibroblasts via protease-activated receptor-2 activation. Am J Pathol. 2008;172(2):309–320.
   PubMed Web of Science ®Google Scholar
• Julovi SM, Xue M, Dervish S, et al. Protease activated receptor-2 mediates activated protein C-induced cutaneous wound healing via inhibition of p38. Am J Pathol. 2011;179(5):2233–2242.
   PubMed Web of Science ®Google Scholar
• Hollenberg MD, Saifeddine M, Al-Ani B. Proteinase-activated receptor-2 in rat aorta: structural requirements for agonist activity of receptor-activating peptides. Mol Pharmacol. 1996;49(2):229–233.
   PubMed Web of Science ®Google Scholar
• Hollenberg MD, Saifeddine M, Al-Ani B, et al. Proteinase-activated receptors: structural requirements for activity, receptor cross-reactivity, and receptor selectivity of receptor-activating peptides. Can J Physiol Pharmacol. 1997;75(7):832–841.
   PubMed Web of Science ®Google Scholar
• Maryanoff BE, Santulli RJ, McComsey DF, et al. Protease-activated receptor-2 (PAR-2): structure-function study of receptor activation by diverse peptides related to tethered-ligand epitopes. Arch Biochem Biophys. 2001;386(2):195–204.
   PubMed Web of Science ®Google Scholar
• McGuire JJ, Saifeddine M, Triggle CR, et al. 2-furoyl-LIGRLO-amide: a potent and selective proteinase-activated receptor 2 agonist. J Pharmacol Exp Ther. 2004;309(3):1124–1131.
   PubMed Web of Science ®Google Scholar
• Barry GD, Suen JY, Low HB, et al. A refined agonist pharmacophore for protease activated receptor 2. Bioorg Med Chem Lett. 2007;17(20):5552–5557.
   PubMed Web of Science ®Google Scholar
• Barry GD, Suen JY, Le GT, et al. Novel agonists and antagonists for human protease activated receptor 2. J Med Chem. 2010;53(20):7428–7440.
   PubMed Web of Science ®Google Scholar
• Peptron Inc. PAR-2 activating peptide derivative with improved biostability and pharmaceutical composition containing it. KR2013034701. 2013.
   Google Scholar
• Vagner J, Qu H, Hruby VJ. Peptidomimetics, a synthetic tool of drug discovery. Curr Opin Chem Biol. 2008;12(3):292–296.
   PubMed Web of Science ®Google Scholar
• Gardell LR, Ma JN, Seitzberg JG, et al. Identification and characterization of novel small-molecule protease-activated receptor 2 agonists. J Pharmacol Exp Ther. 2008;327(3):799–808.
   PubMed Web of Science ®Google Scholar
• Seitzberg JG, Knapp AE, Lund BW, et al. Discovery of potent and selective small-molecule PAR-2 agonists. J Med Chem. 2008;51(18):5490–5493.
   PubMed Web of Science ®Google Scholar
• Flynn AN, Hoffman J, Tillu DV, et al. Development of highly potent protease-activated receptor 2 agonists via synthetic lipid tethering. FASEB J. 2013;27(4):1498–1510.
   PubMed Web of Science ®Google Scholar
• Yau MK, Suen JY, Xu W, et al. Potent small agonists of protease activated receptor 2. ACS Med Chem Lett. 2015;7(1):105–110.
   PubMed Web of Science ®Google Scholar
• The University of Queensland. Modulators of protease activated receptors. US20150038402. 2015.
   Google Scholar
• Al-Ani B, Saifeddine M, Wijesuriya SJ, et al. Modified proteinase-activated receptor-1 and −2 derived peptides inhibit proteinase-activated receptor-2 activation by trypsin. J Pharmacol Exp Ther. 2002;300(2):702–708.
   PubMed Web of Science ®Google Scholar
• Enprani Co. Ltd. Peptides with PAR-2 inhibitory activities for improving skin conditions. KR2011118210. 2011.
   Google Scholar
• Lipotec SA. Peptides which inhibit activated receptors and their use in cosmetic or pharmaceutical compositions. WO2013064583. 2013.
   Google Scholar
• Hadasit Medical Research Services & Development Limited. PAR1 and PAR2 C-tail peptides and peptide mimetics. WO2012090207. 2012.
   Google Scholar
• Kelso EB, Lockhart JC, Hembrough T, et al. Therapeutic promise of proteinase-activated receptor-2 antagonism in joint inflammation. J Pharmacol Exp Ther. 2006;316(3):1017–1024.
   PubMed Web of Science ®Google Scholar
• Kanke T, Kabeya M, Kubo S, et al. Novel antagonists for proteinase-activated receptor 2: inhibition of cellular and vascular responses in vitro and in vivo. Br J Pharmacol. 2009;158(1):361–371.
   PubMed Web of Science ®Google Scholar
• Hoyle GW, Hoyle CI, Chen J, et al. Identification of triptolide, a natural diterpenoid compound, as an inhibitor of lung inflammation. Am J Physiol Lung Cell Mol Physiol. 2010;298(6):L830–L836.
   PubMed Web of Science ®Google Scholar
• Suen JY, Barry GD, Lohman RJ, et al. Modulating human proteinase activated receptor 2 with a novel antagonist (GB88) and agonist (GB110). Br J Pharmacol. 2012;165(5):1413–1423.
   PubMed Web of Science ®Google Scholar
• Boitano S, Hoffman J, Flynn AN, et al. The novel PAR2 ligand C391 blocks multiple PAR2 signalling pathways in vitro and in vivo. Br J Pharmacol. 2015;172(18):4535–4545.
   Web of Science ®Google Scholar
• Cho NC, Cha JH, Kim H, et al. Discovery of 2-aryloxy-4-amino-quinazoline derivatives as novel protease-activated receptor 2 (PAR2) antagonists. Bioorg Med Chem. 2015;23(24):7717–7727.
   PubMed Web of Science ®Google Scholar
• Yau MK, Liu L, Lim J, et al. Benzylamide antagonists of protease activated receptor 2 with anti-inflammatory activity. Bioorg Med Chem Lett. 2016;26(3):986–991.
   PubMed Web of Science ®Google Scholar
• Goh FG, Ng PY, Nilsson M, et al. Dual effect of the novel peptide antagonist K-14585 on proteinase-activated receptor-2-mediated signalling. Br J Pharmacol. 2009;158(7):1695–1704.
   PubMed Web of Science ®Google Scholar
• NeoPharm Co. Ltd. Preparation of piperazine derivative as PAR-2 (protease-activated receptor 2) inhibitor. KR2010038919. 2010.
   Google Scholar
• Proximagen Ltd. Protease activated receptor 2 (par2) antagonists. WO2012101453. 2012.
   Google Scholar
• NeoPharm Co. Ltd. Quinazoline derivative as PAR-2 inhibitor, and method for the preparation thereof. KR20111130259. 2011.
   Google Scholar
• NeoPharm Co. Ltd. Preparation of heterocyclic compounds as PAR-2 inhibitors. WO2012026766. 2012.
   Google Scholar
• Proximagen Ltd. Receptor antagonists. WO2014020351. 2014.
   Google Scholar
• The University of Queensland. Modulators of protease activated receptors. WO2013013273. 2013.
   Google Scholar
• Amorepacific Corp. Preparation of benzothiazine-carboxamides or related compounds as PAR2 inhibitors. KR2015044675. 2015.
   Google Scholar
• Vertex Pharmaceuticals Inc. Imidazopyridazines useful as inhibitors of the PAR2 signaling pathway. WO2015048245. 2015.
   Google Scholar
• Sumitomo Pharma. Novel pyrazolopyrimidine derivatives. WO2005030773. 2005.
   Google Scholar
• The Procter & Gamble Company. Compositions and methods for inhibiting PAR2 activation of keratinocytes. WO2012011908. 2012.
   Google Scholar
• Mullard A. 2014 FDA drug approvals. Nat Rev Drug Discov. 2015;14(2):77–81.
   PubMed Web of Science ®Google Scholar
• Ecker DM, Jones SD, Levine HL. The therapeutic monoclonal antibody market. mAbs. 2015;7(1):9–14.
   PubMed Web of Science ®Google Scholar
• Regeneron Pharmaceuticals Inc. High affinity human antibodies to human protease-activated receptor-2. US20120093824. 2012.
   Google Scholar
• Macdonald LE, Karow M, Stevens S, et al. Precise and in situ genetic humanization of 6 Mb of mouse immunoglobulin genes. Proc Natl Acad Sci USA. 2014;111(14):5147–5152.
   PubMed Web of Science ®Google Scholar
• Murphy AJ, Macdonald LE, Stevens S, et al. Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice. Proc Natl Acad Sci USA. 2014;111(14):5153–5158.
   PubMed Web of Science ®Google Scholar
• Amgen Inc. Antibodies that bind PAR-2. US007888482. 2011.
   Google Scholar
• Amgen Inc. Methods for treating inflammatory conditions using antibodies that bind PAR-2. US008287872. 2012.
   Google Scholar
• Amgen Inc. Antibodies that bind PAR-2. US008357367. 2013.
   Google Scholar
• Amgen Inc. Nucleic acids that encode antigen binding proteins that bind PAR-2. US008470556. 2013.
   Google Scholar
• Boehringer Ingelheim GmbH. Effectors of PAR-2 activation and their use in the modulation of inflammation. WO2010017086. 2010.
   Google Scholar
• Tufts Medical Center Inc. Pepducin design and use. WO2012139137. 2012.
   Google Scholar
• Moffatt JD, Jeffrey KL, Cocks TM. Protease-activated receptor-2 activating peptide SLIGRL inhibits bacterial lipopolysaccharide-induced recruitment of polymorphonuclear leukocytes into the airways of mice. Am J Resp Cell Mol Biol. 2002;26(6):680–684.
   PubMed Web of Science ®Google Scholar