Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Review Article

Advances in the Discovery of Novel Inhaled PI3Kδ Inhibitors for the Treatment of Asthma

Author(s): Jun Wei, Dongyan Gu, Leer Yuan and Rong Sheng*

Volume 30, Issue 17, 2023

Published on: 17 October, 2022

Page: [1971 - 1992] Pages: 22

DOI: 10.2174/0929867329666220819115011

Price: $65

Abstract

Bronchial asthma is the most common chronic respiratory illness, the incidence of which continues to increase annually. Currently, effective treatments for CS-resistant asthma and severe asthma are still lacking, and new therapeutic regimens are urgently required. PI3Kδ is a key enzyme in hematopoietic cells and represents a major target for oncology and inflammatory disease (particularly respiratory disease, asthma and COPD). In the case of respiratory disease, the ability to inhibit PI3Kδ in the lungs shows a higher safety and therapeutic index relative to systemic inhibition. In recent years, paradigm shifts have occurred in inhalation therapeutics for systemic and topical drug delivery due to the favorable properties of lungs, including their large surface area and high permeability. Pulmonary drug delivery possesses many advantages, including a non-invasive route of administration, low metabolic activity, a controlled environment for systemic absorption and the ability to avoid first bypassing metabolism. In this review, we focus on the discovery and development of inhaled drugs targeting PI3Kδ for asthma by focusing on their activity and selectivity, in addition to their potential in drug design strategies using inhaled administration.

Keywords: PI3Ks, inhaled, asthma, lung retention, pharmacokinetic, hematopoietic.

« Previous Next »
[1]
Lazarus, S.C. Clinical practice. Emergency treatment of asthma. N. Engl. J. Med., 2010, 363(8), 755-764.
[http://dx.doi.org/10.1056/NEJMcp1003469] [PMID: 20818877]
[2]
Borish, L.; Culp, J.A.; Asthma, J.A. Asthma: A syndrome composed of heterogeneous diseases. Ann. Allergy Asthma Immunol., 2008, 101(1), 1-8.
[http://dx.doi.org/10.1016/S1081-1206(10)60826-5] [PMID: 18681077]
[3]
Lötvall, J.; Akdis, C.A.; Bacharier, L.B.; Bjermer, L.; Casale, T.B.; Custovic, A.; Lemanske, R.F., Jr; Wardlaw, A.J.; Wenzel, S.E.; Greenberger, P.A. Asthma endotypes: A new approach to classification of disease entities within the asthma syndrome. J. Allergy Clin. Immunol., 2011, 127(2), 355-360.
[http://dx.doi.org/10.1016/j.jaci.2010.11.037] [PMID: 21281866]
[4]
Robinson, D.; Humbert, M.; Buhl, R.; Cruz, A.A.; Inoue, H.; Korom, S.; Hanania, N.A.; Nair, P. Revisiting Type 2-high and Type 2-low airway inflammation in asthma: Current knowledge and therapeutic implications. Clin. Exp. Allergy, 2017, 47(2), 161-175.
[http://dx.doi.org/10.1111/cea.12880] [PMID: 28036144]
[5]
Koshak, E.A. Classification of asthma according to revised 2006 GINA: Evolution from severity to control. Ann. Thorac. Med., 2007, 2(2), 45-46.
[http://dx.doi.org/10.4103/1817-1737.32228] [PMID: 19727344]
[6]
Reddel, H.K.; Bateman, E.D.; Becker, A.; Boulet, L.P.; Cruz, A.A.; Drazen, J.M.; Haahtela, T.; Hurd, S.S.; Inoue, H.; de Jongste, J.C.; Lemanske, R.F., Jr; Levy, M.L.; O’Byrne, P.M.; Paggiaro, P.; Pedersen, S.E.; Pizzichini, E.; Soto-Quiroz, M.; Szefler, S.J.; Wong, G.W.; FitzGerald, J.M. A summary of the new GINA strategy: A roadmap to asthma control. Eur. Respir. J., 2015, 46(3), 622-639.
[http://dx.doi.org/10.1183/13993003.00853-2015] [PMID: 26206872]
[7]
Mathur, S.K.; Viswanathan, R.K. Relevance of allergy in adult asthma. Curr. Allergy Asthma Rep., 2014, 14(5), 437.
[http://dx.doi.org/10.1007/s11882-014-0437-5] [PMID: 24643812]
[8]
de Groot, J.C.; Ten Brinke, A.; Bel, E.H.D. Management of the patient with eosinophilic asthma: A new era begins. ERJ Open Res., 2015, 1(1), 00024.
[http://dx.doi.org/10.1183/23120541.00024-2015] [PMID: 27730141]
[9]
Woodruff, P.G.; Modrek, B.; Choy, D.F.; Jia, G.; Abbas, A.R.; Ellwanger, A.; Koth, L.L.; Arron, J.R.; Fahy, J.V. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am. J. Respir. Crit. Care Med., 2009, 180(5), 388-395.
[http://dx.doi.org/10.1164/rccm.200903-0392OC] [PMID: 19483109]
[10]
Wan, X.C.; Woodruff, P.G. Biomarkers in severe asthma. Immunol. Allergy Clin. North Am., 2016, 36(3), 547-557.
[http://dx.doi.org/10.1016/j.iac.2016.03.004] [PMID: 27401625]
[11]
Jeong, J.S.; Kim, J.S.; Kim, S.R.; Lee, Y.C. Defining bronchial asthma with phosphoinositide 3-kinase delta activation: Towards endotype-driven management. Int. J. Mol. Sci., 2019, 20(14), 3525.
[http://dx.doi.org/10.3390/ijms20143525] [PMID: 31323822]
[12]
Cantley, L.C. The phosphoinositide 3-kinase pathway. Science, 2002, 296(5573), 1655-1657.
[http://dx.doi.org/10.1126/science.296.5573.1655] [PMID: 12040186]
[13]
Foster, J.G.; Blunt, M.D.; Carter, E.; Ward, S.G. Inhibition of PI3K signaling spurs new therapeutic opportunities in inflammatory/autoimmune diseases and hematological malignancies. Pharmacol. Rev., 2012, 64(4), 1027-1054.
[http://dx.doi.org/10.1124/pr.110.004051] [PMID: 23023033]
[14]
Engelman, J.A.; Luo, J.; Cantley, L.C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet., 2006, 7(8), 606-619.
[http://dx.doi.org/10.1038/nrg1879] [PMID: 16847462]
[15]
McNamara, C.R.; Degterev, A. Small-molecule inhibitors of the PI3K signaling network. Future Med. Chem., 2011, 3(5), 549-565.
[http://dx.doi.org/10.4155/fmc.11.12] [PMID: 21526896]
[16]
Rowan, W.C.; Smith, J.L.; Affleck, K.; Amour, A. Targeting phosphoinositide 3-kinase δ for allergic asthma. Biochem. Soc. Trans., 2012, 40(1), 240-245.
[http://dx.doi.org/10.1042/BST20110665] [PMID: 22260698]
[17]
Sriskantharajah, S.; Hamblin, N.; Worsley, S.; Calver, A.R.; Hessel, E.M.; Amour, A. Targeting phosphoinositide 3-kinase δ for the treatment of respiratory diseases. Ann. N. Y. Acad. Sci., 2013, 1280(1), 35-39.
[http://dx.doi.org/10.1111/nyas.12039] [PMID: 23551101]
[18]
Ball, J.; Archer, S.; Ward, S. PI3K inhibitors as potential therapeutics for autoimmune disease. Drug Discov. Today, 2014, 19(8), 1195-1199.
[http://dx.doi.org/10.1016/j.drudis.2014.04.002] [PMID: 24735732]
[19]
Kim, S.R.; Lee, K.S.; Park, H.S.; Park, S.J.; Min, K.H.; Moon, H.; Puri, K.D.; Lee, Y.C. HIF-1α inhibition ameliorates an allergic airway disease via VEGF suppression in bronchial epithelium. Eur. J. Immunol., 2010, 40(10), 2858-2869.
[http://dx.doi.org/10.1002/eji.200939948] [PMID: 20827786]
[20]
Lambrecht, B.N.; Hammad, H. The immunology of asthma. Nat. Immunol., 2015, 16(1), 45-56.
[http://dx.doi.org/10.1038/ni.3049] [PMID: 25521684]
[21]
Lee, K.S.; Lee, H.K.; Hayflick, J.S.; Lee, Y.C.; Puri, K.D. Inhibition of phosphoinositide 3-kinase δ attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model. FASEB J., 2006, 20(3), 455-465.
[http://dx.doi.org/10.1096/fj.05-5045com] [PMID: 16507763]
[22]
Farghaly, H.S.M.; Blagbrough, I.S.; Medina-Tato, D.A.; Watson, M.L. Interleukin 13 increases contractility of murine tracheal smooth muscle by a phosphoinositide 3-kinase p110δ-dependent mechanism. Mol. Pharmacol., 2008, 73(5), 1530-1537.
[http://dx.doi.org/10.1124/mol.108.045419] [PMID: 18276774]
[23]
Ray, A.; Kolls, J.K. Neutrophilic inflammation in asthma and association with disease severity. Trends Immunol., 2017, 38(12), 942-954.
[http://dx.doi.org/10.1016/j.it.2017.07.003] [PMID: 28784414]
[24]
Ito, K.; Ito, M.; Elliott, W.M.; Cosio, B.; Caramori, G.; Kon, O.M.; Barczyk, A.; Hayashi, S.; Adcock, I.M.; Hogg, J.C.; Barnes, P.J. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N. Engl. J. Med., 2005, 352(19), 1967-1976.
[http://dx.doi.org/10.1056/NEJMoa041892] [PMID: 15888697]
[25]
Barnes, P.J. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J. Allergy Clin. Immunol., 2013, 131(3), 636-645.
[http://dx.doi.org/10.1016/j.jaci.2012.12.1564] [PMID: 23360759]
[26]
Park, S.W.; Zhou, Y.; Lee, J.; Lu, A.; Sun, C.; Chung, J.; Ueki, K.; Ozcan, U. The regulatory subunits of PI3K, p85α and p85β, interact with XBP-1 and increase its nuclear translocation. Nat. Med., 2010, 16(4), 429-437.
[http://dx.doi.org/10.1038/nm.2099] [PMID: 20348926]
[27]
McKinley, L.; Alcorn, J.F.; Peterson, A.; Dupont, R.B.; Kapadia, S.; Logar, A.; Henry, A.; Irvin, C.G.; Piganelli, J.D.; Ray, A.; Kolls, J.K. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J. Immunol., 2008, 181(6), 4089-4097.
[http://dx.doi.org/10.4049/jimmunol.181.6.4089] [PMID: 18768865]
[28]
Lee, K.S.; Jeong, J.S.; Kim, S.R.; Cho, S.H.; Kolliputi, N.; Ko, Y.H.; Lee, K.B.; Park, S.C.; Park, H.J.; Lee, Y.C. Phosphoinositide 3-kinase-δ regulates fungus-induced allergic lung inflammation through endoplasmic reticulum stress. Thorax, 2016, 71(1), 52-63.
[http://dx.doi.org/10.1136/thoraxjnl-2015-207096] [PMID: 26543090]
[29]
Perry, M.W.D.; Abdulai, R.; Mogemark, M.; Petersen, J.; Thomas, M.J.; Valastro, B.; Westin Eriksson, A. Evolution of PI3Kγ and δ inhibitors for inflammatory and autoimmune diseases. J. Med. Chem., 2019, 62(10), 4783-4814.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01298] [PMID: 30582813]
[30]
Feng, Y.; Cu, X.; Xin, M. PI3Kδ inhibitors for the treatment of cancer: A patent review (2015-present). Expert Opin. Ther. Pat., 2019, 29(12), 925-941.
[http://dx.doi.org/10.1080/13543776.2019.1687685] [PMID: 31670985]
[31]
Sun, J.; Feng, Y.; Huang, Y.; Zhang, S.Q.; Xin, M. Research advances on selective phosphatidylinositol 3 kinase δ (PI3Kδ) inhibitors. Bioorg. Med. Chem. Lett., 2020, 30(19), 127457.
[http://dx.doi.org/10.1016/j.bmcl.2020.127457] [PMID: 32755681]
[32]
Garces, A.E.; Stocks, M.J. Class 1 PI3K clinical candidates and recent inhibitor design strategies: A medicinal chemistry perspective. J. Med. Chem., 2019, 62(10), 4815-4850.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01492] [PMID: 30582807]
[33]
Elmenier, F.M.; Lasheen, D.S.; Abouzid, K.A.M. Phosphatidylinositol 3 kinase (PI3K) inhibitors as new weapon to combat cancer. Eur. J. Med. Chem., 2019, 183, 111718.
[http://dx.doi.org/10.1016/j.ejmech.2019.111718] [PMID: 31581005]
[34]
Cheah, C.Y.; Fowler, N.H. Idelalisib in the management of lymphoma. Blood, 2016, 128(3), 331-336.
[http://dx.doi.org/10.1182/blood-2016-02-702761] [PMID: 27252232]
[35]
Iskierka-Jażdżewska, E.; Robak, T. Investigational treatments for chronic lymphocytic leukemia: A focus on phase 1 and 2 clinical trials. Expert Opin. Investig. Drugs, 2020, 29(7), 709-722.
[http://dx.doi.org/10.1080/13543784.2020.1770225] [PMID: 32407139]
[36]
ClinicalTrials.gov. Study to assess the efficacy and safety of ublituximab + umbralisib with or without bendamustine and umbralisib alone in patients with previously treated non-hodgkins lymphoma. NCT02793583, 2016.
[37]
Mato, A.R.; Ghosh, N.; Schuster, S.J.; Lamanna, N.; Pagel, J.M.; Flinn, I.W.; Barrientos, J.C.; Rai, K.R.; Reeves, J.A.; Cheson, B.D.; Barr, P.M.; Kambhampati, S.; Lansigan, F.; Pu, J.J.; Skarbnik, A.P.; Roeker, L.; Fonseca, G.A.; Sitlinger, A.; Hamadeh, I.S.; Dorsey, C.; LaRatta, N.; Weissbrot, H.; Luning Prak, E.T.; Tsao, P.; Paskalis, D.; Sportelli, P.; Miskin, H.P.; Weiss, M.S.; Svoboda, J.; Brander, D.M. Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who are intolerant to BTK or PI3Kδ inhibitor therapy. Blood, 2021, 137(20), 2817-2826.
[http://dx.doi.org/10.1182/blood.2020007376] [PMID: 33259589]
[38]
ClinicalTrial.gov. Ublituximab + tgr-1202 compared to obinutuzumab + chlorambucil in patients with untreated and previously treated chronic lymphocytic leukemia. NCT02612311, 2015.
[39]
ClinicalTrial.gov. Acerta pharma BV, acalabrutinib in combination with ACP-319, for treatment of chronic lymphocytic leukemia. NCT02157324, 2014.
[40]
ClinicalTrial.gov. Acerta pharma BV, acalabrutinib (ACP-196) in combination with ACP-319, for treatment of B-cell malignancies. NCT02328014, 2014.
[41]
Batlevi, C.L.; Younes, A. Revival of PI3K inhibitors in non-hodgkin’s lymphoma. Ann. Oncol., 2017, 28(9), 2047-2049.
[http://dx.doi.org/10.1093/annonc/mdx392] [PMID: 28911078]
[42]
Cushing, T.D.; Hao, X.; Shin, Y.; Andrews, K.; Brown, M.; Cardozo, M.; Chen, Y.; Duquette, J.; Fisher, B.; Gonzalez-Lopez de Turiso, F.; He, X.; Henne, K.R.; Hu, Y.L.; Hungate, R.; Johnson, M.G.; Kelly, R.C.; Lucas, B.; McCarter, J.D.; McGee, L.R.; Medina, J.C.; San Miguel, T.; Mohn, D.; Pattaropong, V.; Pettus, L.H.; Reichelt, A.; Rzasa, R.M.; Seganish, J.; Tasker, A.S.; Wahl, R.C.; Wannberg, S.; Whittington, D.A.; Whoriskey, J.; Yu, G.; Zalameda, L.; Zhang, D.; Metz, D.P. Discovery and in vivo evaluation of (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and related PI3Kδ inhibitors for inflammation and autoimmune disease. J. Med. Chem., 2015, 58(1), 480-511.
[http://dx.doi.org/10.1021/jm501624r] [PMID: 25469863]
[43]
ClinicalTrial.gov. Study of INCB040093 in subjects with previously treated B-Cell malignancies. NCT01905813, 2013.
[44]
ClinicalTrial.gov. Incyte corporation, a phase 1/2, open-label, dose escalation, safety and tolerability study of INCB050465 and itacitinib in subjects with previously treated B-Cell malignancies (CITADEL-101). NCT02018861, 2013.
[45]
O’Farrell, M.; Ventura, R.; Tai, A.; Tyner, J.W.; Loriaux, M.M.; Mahadevan, D.; Morales, C.; Brown, S.D.; Matthews, D.J. Preclinical characterization of PWT143, a novel selective and potent phosphatidylinositol 3-kinase delta (PI3K Delta) inhibitor with ex-vivo activity in hematologic malignancies. Blood, 2012, 120(21), 2907-2907.
[http://dx.doi.org/10.1182/blood.V120.21.2907.2907]
[46]
Allen, R.A.; Brookings, D.C.; Powell, M.J.; Delgado, J.; Shuttleworth, L.K.; Merriman, M.; Fahy, I.J.; Tewari, R.; Silva, J.P.; Healy, L.J.; Davies, G.C.G.; Twomey, B.; Cutler, R.M.; Kotian, A.; Crosby, A.; McCluskey, G.; Watt, G.F.; Payne, A. Seletalisib: Characterization of a novel, potent, and selective inhibitor of PI3Kδ. J. Pharmacol. Exp. Ther., 2017, 361(3), 429-440.
[http://dx.doi.org/10.1124/jpet.116.237347] [PMID: 28442583]
[47]
Rao, V.K.; Webster, S.; Dalm, V.A.S.H.; Šedivá, A.; van Hagen, P.M.; Holland, S.; Rosenzweig, S.D.; Christ, A.D.; Sloth, B.; Cabanski, M.; Joshi, A.D.; de Buck, S.; Doucet, J.; Guerini, D.; Kalis, C.; Pylvaenaeinen, I.; Soldermann, N.; Kashyap, A.; Uzel, G.; Lenardo, M.J.; Patel, D.D.; Lucas, C.L.; Burkhart, C. Effective “activated PI3Kδ syndrome”-targeted therapy with the PI3Kδ inhibitor leniolisib. Blood, 2017, 130(21), 2307-2316.
[http://dx.doi.org/10.1182/blood-2017-08-801191] [PMID: 28972011]
[48]
Horwitz, S.M.; Koch, R.; Porcu, P.; Oki, Y.; Moskowitz, A.; Perez, M.; Myskowski, P.; Officer, A.; Jaffe, J.D.; Morrow, S.N.; Allen, K.; Douglas, M.; Stern, H.; Sweeney, J.; Kelly, P.; Kelly, V.; Aster, J.C.; Weaver, D.; Foss, F.M.; Weinstock, D.M. Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. Blood, 2018, 131(8), 888-898.
[http://dx.doi.org/10.1182/blood-2017-08-802470] [PMID: 29233821]
[49]
Schmalbach, T.; Fuhr, R.; Allen, A.M.; Douglas, K.; Dunbar, M.; McLaughlin, J.; Alexander, J.; McKee, L.; Duvelisib, C. A PI3K-δ,γ inhibitor, in subjects with mild asthma. Eur. Respir. J. Eur. Respir. Soc., 2015, 46(59), 2122.
[50]
Leff, R.; Kumar, S.; Nikulenkova, N.; Kaidashev, I.; Allen, K.; Dunbar, J.; Stern, H.; Adams, J.; Weinblatt, M. Safety and efficacy results of a phase 2, double-blind, placebo-controlled clinical study of duvelisib with background methotrexate (MTX) in adults with moderate-to-severe rheumatoid arthritis (RA) - ACR meeting abstracts. Arthritis Rheumatol., 2015, 67(Suppl. 10), 2138.
[51]
Winkler, D.G.; Faia, K.L.; DiNitto, J.P.; Ali, J.A.; White, K.F.; Brophy, E.E.; Pink, M.M.; Proctor, J.L.; Lussier, J.; Martin, C.M.; Hoyt, J.G.; Tillotson, B.; Murphy, E.L.; Lim, A.R.; Thomas, B.D.; Macdougall, J.R.; Ren, P.; Liu, Y.; Li, L.S.; Jessen, K.A.; Fritz, C.C.; Dunbar, J.L.; Porter, J.R.; Rommel, C.; Palombella, V.J.; Changelian, P.S.; Kutok, J.L. PI3K-δ and PI3K-γ inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem. Biol., 2013, 20(11), 1364-1374.
[http://dx.doi.org/10.1016/j.chembiol.2013.09.017] [PMID: 24211136]
[52]
ClinicalTrial.gov. Rhizen pharmaceuticals SA, safety and efficacy study of tenalisib (RP6530) in combination with pembrolizumab in relapsed or refractory CHL. NCT03471351, 2018.
[53]
Huen, A.; Haverkos, B.M.; Zain, J.; Radhakrishnan, R.; Lechowicz, M.J.; Devata, S.; Korman, N.J.; Pinter-Brown, L.; Oki, Y.; Barde, P.J.; Nair, A.; Routhu, K.V.; Viswanadha, S.; Vakkalanka, S.; Iyer, S.P. Phase I/Ib study of tenalisib (RP6530), a dual PI3K δ/γ inhibitor in patients with relapsed/refractory T-cell lymphoma. Cancers (Basel), 2020, 12(8), 2293-2306.
[http://dx.doi.org/10.3390/cancers12082293]
[54]
Coutré, S.E.; Barrientos, J.C.; Brown, J.R.; de Vos, S.; Furman, R.R.; Keating, M.J.; Li, D.; O’Brien, S.M.; Pagel, J.M.; Poleski, M.H.; Sharman, J.P.; Yao, N.S.; Zelenetz, A.D. Management of adverse events associated with idelalisib treatment: Expert panel opinion. Leuk. Lymphoma, 2015, 56(10), 2779-2786.
[http://dx.doi.org/10.3109/10428194.2015.1022770] [PMID: 25726955]
[55]
Davies, D.S. Pharmacokinetics of inhaled substances. Postgrad. Med. J., 1975, 51(7 Suppl.), 69-75.
[PMID: 822405]
[56]
Cooper, A.E.; Ferguson, D.; Grime, K. Optimisation of DMPK by the inhaled route: Challenges and approaches. Curr. Drug Metab., 2012, 13(4), 457-473.
[http://dx.doi.org/10.2174/138920012800166571] [PMID: 22299825]
[57]
Patton, J.S.; Byron, P.R. Inhaling medicines: Delivering drugs to the body through the lungs. Nat. Rev. Drug Discov., 2007, 6(1), 67-74.
[http://dx.doi.org/10.1038/nrd2153] [PMID: 17195033]
[58]
Anderson, P.J. Delivery options and devices for aerosolized therapeutics. Chest, 2001, 120(3), 89S-93S.
[http://dx.doi.org/10.1378/chest.120.3_suppl.89S] [PMID: 11555561]
[59]
Felding, J.; Sørensen, M.D.; Poulsen, T.D.; Larsen, J.; Andersson, C.; Refer, P.; Engell, K.; Ladefoged, L.G.; Thormann, T.; Vinggaard, A.M.; Hegardt, P.; Søhoel, A.; Nielsen, S.F. Discovery and early clinical development of 2-{6-[2-(3,5-dichloro-4-pyridyl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (LEO29102), a soft-drug Inhibitor of phosphodiesterase 4 for topical treatment of atopic dermatitis. J. Med. Chem., 2014, 57, 5893-5903.
[http://dx.doi.org/10.1021/jm500378a] [PMID: 24984230]
[60]
Bodor, N.; Buchwald, P. Soft drug design: General principles and recent applications. Med. Res. Rev., 2000, 20(1), 58-101.
[http://dx.doi.org/10.1002/(SICI)1098-1128(200001)20:1<58::AID-MED3>3.0.CO;2-X] [PMID: 10608921]
[61]
LüllmannRauch, R. History and morphology of the lysosome. Lysosomes; Springer: US, 2005.
[62]
Cooper, A.; Potter, T.; Luker, T. Prediction of efficacious inhalation lung doses via the use of in silico lung retention quantitative structure-activity relationship models and in vitro potency screens. Drug Metab. Dispos., 2010, 38(12), 2218-2225.
[http://dx.doi.org/10.1124/dmd.110.034462] [PMID: 20823295]
[63]
Erra, M.; Taltavull, J.; Bernal, F.J.; Caturla, J.F.; Carrascal, M.; Pagès, L.; Mir, M.; Espinosa, S.; Gràcia, J.; Domínguez, M.; Sabaté, M.; Paris, S.; Maldonado, M.; Hernández, B.; Bravo, M.; Calama, E.; Miralpeix, M.; Lehner, M.D.; Calbet, M. Discovery of a novel inhaled PI3Kδ inhibitor for the treatment of respiratory diseases. J. Med. Chem., 2018, 61(21), 9551-9567.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00873] [PMID: 30351000]
[64]
Hochhaus, G.; Möllmann, H.; Derendorf, H.; Gonzalez-Rothi, R.J. Pharmacokinetic/pharmacodynamic aspects of aerosol therapy using glucocorticoids as a model. J. Clin. Pharmacol., 1997, 37(10), 881-892.
[http://dx.doi.org/10.1002/j.1552-4604.1997.tb04262.x] [PMID: 9505979]
[65]
Hochhaus, G.; Gonzalez-Rothi, R.J.; Lukyanov, A.; Derendorf, H.; Schreier, H.; Dalla Costa, T. Assessment of glucocorticoid lung targeting by ex-vivo receptor binding studies in rats. Pharm. Res., 1995, 12(1), 134-137.
[http://dx.doi.org/10.1023/A:1016259225244] [PMID: 7724475]
[66]
Anttila, S.; Tuominen, P.; Hirvonen, A.; Nurminen, M.; Karjalainen, A.; Hankinson, O.; Elovaara, E. CYP1A1 levels in lung tissue of tobacco smokers and polymorphisms of CYP1A1 and aromatic hydrocarbon receptor. Pharmacogenetics, 2001, 11(6), 501-509.
[http://dx.doi.org/10.1097/00008571-200108000-00005] [PMID: 11505220]
[67]
Anttila, S.; Hakkola, J.; Tuominen, P.; Elovaara, E.; Husgafvel-Pursiainen, K.; Karjalainen, A.; Hirvonen, A.; Nurminen, T. Methylation of cytochrome P4501A1 promoter in the lung is associated with tobacco smoking. Cancer Res., 2003, 63(24), 8623-8628.
[PMID: 14695173]
[68]
Kim, J.H.; Sherman, M. E.; Curriero, F. C.; Guengerich, F. P.; Strickland, P. T.; Sutter, T. R. Expression of cytochrome P450 1A1 and 1B1 in human lung from smoker, non-smokers and ex-smokers. Toxicol. Appl. Pharmacol., 2004, 199, 210-219.
[http://dx.doi.org/10.1016/j.taap.2003.11.015] [PMID: 15364538]
[69]
Peters, R. From fluorescence nanoscopy to nanoscopic medicine. Nanomedicine (Lond.), 2008, 3(1), 1-4.
[http://dx.doi.org/10.2217/17435889.3.1.1] [PMID: 18393640]
[70]
Champion, J.A.; Walker, A.; Mitragotri, S. Role of particle size in phagocytosis of polymeric microspheres. Pharm. Res., 2008, 25(8), 1815-1821.
[http://dx.doi.org/10.1007/s11095-008-9562-y] [PMID: 18373181]
[71]
Usmani, O.S.; Biddiscombe, M.F.; Underwood, S.R.; Barnes, P.J. Characterization of the generation of radiolabeled monodisperse albuterol particles using the spinning-top aerosol generator. J. Nucl. Med., 2004, 45(1), 69-73.
[PMID: 14734675]
[72]
Champion, J.A.; Mitragotri, S. Shape induced inhibition of phagocytosis of polymer particles. Pharm. Res., 2009, 26(1), 244-249.
[http://dx.doi.org/10.1007/s11095-008-9626-z] [PMID: 18548338]
[73]
Harris, J.M.; Chess, R.B. Effect of pegylation on pharmaceuticals. Nat. Rev. Drug Discov., 2003, 2(3), 214-221.
[http://dx.doi.org/10.1038/nrd1033] [PMID: 12612647]
[74]
Surendrakumar, K.; Martyn, G.P.; Hodgers, E.C.M.; Jansen, M.; Blair, J.A. Sustained release of insulin from sodium hyaluronate based dry powder formulations after pulmonary delivery to beagle dogs. J. Control. Release, 2003, 91(3), 385-394.
[http://dx.doi.org/10.1016/S0168-3659(03)00263-3] [PMID: 12932716]
[75]
Evora, C.; Soriano, I.; Rogers, R.A.; Shakesheff, K.N.; Hanes, J.; Langer, R. Relating the phagocytosis of microparticles by alveolar macrophages to surface chemistry: The effect of 1,2-dipalmitoylphosphatidylcholine. J. Control. Release, 1998, 51(2-3), 143-152.
[http://dx.doi.org/10.1016/S0168-3659(97)00149-1] [PMID: 9685911]
[76]
Hickey, A. J. Pharmaceutical inhalation aerosol technology; Taylor & Francis Group: UK, 2004.
[77]
Niven, R.W.; Whitcomb, K.L.; Shaner, L.; Ip, A.Y.; Kinstler, O.B. The pulmonary absorption of aerosolized and intratracheally instilled rhG-CSF and monoPEGylated rhG-CSF. Pharm. Res., 1995, 12(9), 1343-1349.
[http://dx.doi.org/10.1023/A:1016281925554] [PMID: 8570533]
[78]
Meenach, S.A.; Vogt, F.G.; Anderson, K.W.; Hilt, J.Z.; McGarry, R.C.; Mansour, H.M. Design, physicochemical characterization, and optimization of organic solution advanced spray-dried inhalable dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine poly(ethylene glycol) (DPPE-PEG) microparticles and nanoparticles for targeted respiratory nanomedicine delivery as dry powder inhalation aerosols. Int. J. Nanomedicine, 2013, 8, 275-293.
[PMID: 23355776]
[79]
Suzuki, Y.; Yamaguchi, T. Effects of hyaluronic acid on macrophage phagocytosis and active oxygen release. Agents Actions, 1993, 38(1-2), 32-37.
[http://dx.doi.org/10.1007/BF02027210] [PMID: 8386900]
[80]
Down, K.; Amour, A.; Baldwin, I.R.; Cooper, A.W.; Deakin, A.M.; Felton, L.M.; Guntrip, S.B.; Hardy, C.; Harrison, Z.A.; Jones, K.L.; Jones, P.; Keeling, S.E.; Le, J.; Livia, S.; Lucas, F.; Lunniss, C.J.; Parr, N.J.; Robinson, E.; Rowland, P.; Smith, S.; Thomas, D.A.; Vitulli, G.; Washio, Y.; Hamblin, J.N. Optimization of novel indazoles as highly potent and selective inhibitors of phosphoinositide 3-kinase δ for the treatment of respiratory disease. J. Med. Chem., 2015, 58(18), 7381-7399.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00767] [PMID: 26301626]
[81]
GlaxoSmithKline. A study to investigate the efficacy, safety, and tolerability of repeat doses of inhaled GSK2269557 in adults with persistent, uncontrolled asthma NCT02567708, 2015.
[82]
GlaxoSmithKline. A study to evaluate the safety, efficacy and changes in induced sputum and blood biomarkers following daily repeat doses of inhaled GSK2269557 in chronic obstructive pulmonary disease (COPD) subjects with acute exacerbation. NCT02522299, 2015.
[83]
Wilson, R.; Templeton, A.; Leemereise, C.; Eames, R.; Banham-Hall, E.; Hessel, E.M.; Cahn, A. Safety, tolerability, and pharmacokinetics of a new formulation of Nemiralisib administered via a dry powder inhaler to healthy individuals. Clin. Ther., 2019, 41(6), 1214-1220.
[http://dx.doi.org/10.1016/j.clinthera.2019.04.008] [PMID: 31076203]
[84]
Knight, S.D.; Adams, N.D.; Burgess, J.L.; Chaudhari, A.M.; Darcy, M.G.; Donatelli, C.A.; Luengo, J.I.; Newlander, K.A.; Parrish, C.A.; Ridgers, L.H.; Sarpong, M.A.; Schmidt, S.J.; Van Aller, G.S.; Carson, J.D.; Diamond, M.A.; Elkins, P.A.; Gardiner, C.M.; Garver, E.; Gilbert, S.A.; Gontarek, R.R.; Jackson, J.R.; Kershner, K.L.; Luo, L.; Raha, K.; Sherk, C.S.; Sung, C.M.; Sutton, D.; Tummino, P.J.; Wegrzyn, R.J.; Auger, K.R.; Dhanak, D. Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian target of rapamycin. ACS Med. Chem. Lett., 2010, 1(1), 39-43.
[http://dx.doi.org/10.1021/ml900028r] [PMID: 24900173]
[85]
GlaxoSmithKline. Safety, tolerability and pharmacokinetics of single and repeat doses of GSK2292767 in healthy participants who smoke cigarettes. NCT03045887, 2017.
[86]
Thomas, M.; Edwards, M.J.; Sawicka, E.; Duggan, N.; Hirsch, E.; Wymann, M.P.; Owen, C.; Trifilieff, A.; Walker, C.; Westwick, J.; Finan, P. Essential role of phosphoinositide 3-kinase gamma in eosinophil chemotaxis within acute pulmonary inflammation. Immunology, 2009, 126(3), 413-422.
[http://dx.doi.org/10.1111/j.1365-2567.2008.02908.x] [PMID: 18754810]
[87]
Sala, V.; Della Sala, A.; Ghigo, A.; Hirsch, E. Roles of phosphatidyl inositol 3 kinase gamma (PI3Kγ) in respiratory diseases. Cell Stress, 2021, 5(4), 40-51.
[http://dx.doi.org/10.15698/cst2021.04.246] [PMID: 33821232]
[88]
Norman, P. Evaluation of WO2013136076: Two crystalline forms of the phosphatidylinositol 3-kinase-δ inhibitor RV-1729. Expert Opin. Ther. Pat., 2014, 24(4), 471-475.
[http://dx.doi.org/10.1517/13543776.2014.865725] [PMID: 24283201]
[89]
John, K.; Kazuhiro, I.; John, M. P.; George, H.; Arthur, B. F.; John, B. C. Quinazolin-4(3H)-one derivatives used as PI3 kinase inhibitors. WO2012052753A1, 2012.
[90]
Respivert Ltd. A study to investigate the safety, tolerability and pharmacokinetics of single and repeat doses of RV1729 for up to 28 Days. NCT02140320, 2014.
[91]
Respivert Ltd. A study to investigate the safety, tolerability and pharmacokinetics of single and repeat doses of RV1729 for up to 28 Days in patients with COPD. NCT02140346, 2014.
[92]
Respivert Ltd. A study to investigate the safety, tolerability and pharmacokinetics of single and repeat doses of RV6153. NCT02517359, 2015.
[93]
Perry, M.W.D.; Björhall, K.; Bold, P.; Brűlls, M.; Börjesson, U.; Carlsson, J.; Chang, H.A.; Chen, Y.; Eriksson, A.; Fihn, B.M.; Fransson, R.; Fredlund, L.; Ge, H.; Huang, H.; Karabelas, K.; Lamm Bergström, E.; Lever, S.; Lindmark, H.; Mogemark, M.; Nikitidis, A.; Palmgren, A.P.; Pemberton, N.; Petersen, J.; Rodrigo Blomqvist, M.; Smith, R.W.; Thomas, M.J.; Ullah, V.; Tyrchan, C.; Wennberg, T.; Westin Eriksson, A.; Yang, W.; Zhao, S.; Öster, L. Discovery of AZD8154, a dual PI3Kγδ inhibitor for the treatment of asthma. J. Med. Chem., 2021, 64(12), 8053-8075.
[http://dx.doi.org/10.1021/acs.jmedchem.1c00434] [PMID: 34080862]
[94]
Pemberton, N.; Mogemark, M.; Arlbrandt, S.; Bold, P.; Cox, R.J.; Gardelli, C.; Holden, N.S.; Karabelas, K.; Karlsson, J.; Lever, S.; Li, X.; Lindmark, H.; Norberg, M.; Perry, M.W.D.; Petersen, J.; Rodrigo Blomqvist, S.; Thomas, M.; Tyrchan, C.; Westin Eriksson, A.; Zlatoidsky, P.; Öster, L. Discovery of highly isoform selective orally bioavailable phosphoinositide 3-kinase (PI3K)-γ inhibitors. J. Med. Chem., 2018, 61(12), 5435-5441.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00447] [PMID: 29852070]
[95]
Sadiq, M.W.; Asimus, S.; Belvisi, M.G.; Brailsford, W.; Fransson, R.; Fuhr, R.; Hagberg, A.; Hashemi, M.; Jellesmark Jensen, T.; Jonsson, J.; Keen, C.; Körnicke, T.; Kristensson, C.; Mäenpää, J.; Necander, S.; Nemes, S.; Betts, J. Characterisation of pharmacokinetics, safety and tolerability in a first-in-human study for AZD8154, a novel inhaled selective PI3Kγδ dual inhibitor targeting airway inflammatory disease. Br. J. Clin. Pharmacol., 2022, 88(1), 260-270.
[http://dx.doi.org/10.1111/bcp.14956] [PMID: 34182611]
[96]
Perry, M.W.D.; Björhall, K.; Bonn, B.; Carlsson, J.; Chen, Y.; Eriksson, A.; Fredlund, L.; Hao, H.; Holden, N.S.; Karabelas, K.; Lindmark, H.; Liu, F.; Pemberton, N.; Petersen, J.; Rodrigo Blomqvist, S.; Smith, R.W.; Svensson, T.; Terstiege, I.; Tyrchan, C.; Yang, W.; Zhao, S.; Öster, L. Design and synthesis of soluble and cell-permeable PI3Kδ inhibitors for long-acting inhaled administration. J. Med. Chem., 2017, 60(12), 5057-5071.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00401] [PMID: 28520415]
[97]
Li, F.; Liang, X.; Jiang, Z.; Wang, A.; Wang, J.; Chen, C.; Wang, W.; Zou, F.; Qi, Z.; Liu, Q.; Hu, Z.; Cao, J.; Wu, H.; Wang, B.; Wang, L.; Liu, J.; Liu, Q. Discovery of (S)-2-(1-(4-Amino-3-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)-3-cyclopropyl-5-fluoroquinazolin-4(3H)-one (IHMT-PI3Kδ-372) as a potent and selective pi3kδ inhibitor for the treatment of chronic obstructive pulmonary disease. J. Med. Chem., 2020, 63(22), 13973-13993.
[http://dx.doi.org/10.1021/acs.jmedchem.0c01544] [PMID: 33180507]
[98]
Khindri, S.; Cahn, A.; Begg, M.; Montembault, M.; Leemereise, C.; Cui, Y.; Hogg, A.; Wajdner, H.; Yang, S.; Robertson, J.; Hamblin, J. N.; Ludwig-Sengpiel, A.; Kornmann, O.; Hessel, E. M. A multicentre, randomised, double-blind, placebo-controlled, crossover study to investigate the efficacy, safety, tolerability and pharmacokinetics of repeat doses of inhaled Nemiralisib in adults with persistent, uncontrolled asthma. J. Pharmacol. Exp. Ther., 2018, 367, 405-413.
[http://dx.doi.org/10.1124/jpet.118.249516] [PMID: 30217958]
[99]
Jin, F.; Robeson, M.; Zhou, H.; Moyer, C.; Wilbert, S.; Murray, B.; Ramanathan, S. Clinical drug interaction profile of idelalisib in healthy subjects. J. Clin. Pharmacol., 2015, 55(8), 909-919.
[http://dx.doi.org/10.1002/jcph.495] [PMID: 25760671]
[100]
Ramanathan, S.; Jin, F.; Sharma, S.; Kearney, B.P. Clinical pharmacokinetic and pharmacodynamic profile of idelalisib. Clin. Pharmacokinet., 2016, 55(1), 33-45.
[http://dx.doi.org/10.1007/s40262-015-0304-0] [PMID: 26242379]

Rights & Permissions Print Cite
Article Metrics
120
5
World Chagas Disease
© 2024 Bentham Science Publishers | Privacy Policy