Login Register Cart 0
Review Article

2011~2021年批准的GPCR靶向药物的构效关系

卷 30, 期 31, 2023

发表于: 19 December, 2022

页: [3527 - 3549] 页: 23

弟呕挨: 10.2174/1573399819666221102113217

价格: $65

conference banner
摘要

背景：G蛋白偶联受体(GPCR)是最大的膜受体家族，也是研究最深入的药物靶点。鉴于GPCR信号转导在生理上的重要性以及近年来在膜蛋白结构测定方面的进展，GPCR拮抗剂和激动剂的开发有望继续成为药物化学研究的一个重要领域。 方法：构效关系说明了化学结构的改变如何影响药物化合物的吸收、分布、代谢、排泄和其他相关性质。了解临床批准的GPCR靶向药物及其类似物的结构-性质关系可以为候选药物的先导优化策略提供有用的信息。 结果：在过去十年批准的50多种GPCR拮抗剂和激动剂中，从药物化学文献中整理了17种药物的构效关系，其中不仅披露了最终候选药物的详细药代动力学和毒理学性质，还披露了在先导优化过程中产生的关键类似物。 结论：本文总结的构效关系表明，在许多情况下，膜蛋白靶向配体的体外和体内性能可以有效优化，而不需要显著改变分子大小。这一信息有望为加快新的GPCR靶向药物的开发提供有价值的见解。

关键词: 构效关系，GPCR拮抗剂，GPCR激动剂，先导物优化，候选物选择，药物发现。

« Previous Next »
[1]
Kobilka, B. The structural basis of G-protein-coupled receptor signaling. Angew. Chem. Int. Ed., 2013, 52(25), 6380-6388.
[http://dx.doi.org/10.1002/anie.201302116] [PMID: 23650120]
[2]
Lagerström, M.C.; Schiöth, H.B. Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat. Rev. Drug Discov., 2008, 7(4), 339-357.
[http://dx.doi.org/10.1038/nrd2518] [PMID: 18382464]
[3]
Lee, S.M.; Booe, J.M.; Pioszak, A.A. Structural insights into ligand recognition and selectivity for classes A, B, and C GPCRs. Eur. J. Pharmacol., 2015, 763(Pt B), 196-205.
[http://dx.doi.org/10.1016/j.ejphar.2015.05.013] [PMID: 25981303]
[4]
Wacker, D.; Stevens, R.C.; Roth, B.L. How ligands illuminate GPCR molecular pharmacology. Cell, 2017, 170(3), 414-427.
[http://dx.doi.org/10.1016/j.cell.2017.07.009] [PMID: 28753422]
[5]
Latorraca, N.R.; Venkatakrishnan, A.J.; Dror, R.O. GPCR dynamics: Structures in motion. Chem. Rev., 2017, 117(1), 139-155.
[http://dx.doi.org/10.1021/acs.chemrev.6b00177] [PMID: 27622975]
[6]
Hilger, D.; Masureel, M.; Kobilka, B.K. Structure and dynamics of GPCR signaling complexes. Nat. Struct. Mol. Biol., 2018, 25(1), 4-12.
[http://dx.doi.org/10.1038/s41594-017-0011-7] [PMID: 29323277]
[7]
Hilger, D. The role of structural dynamics in GPCR-mediated signaling. FEBS J., 2021, 288(8), 2461-2489.
[http://dx.doi.org/10.1111/febs.15841] [PMID: 33871923]
[8]
Inoue, A.; Raimondi, F.; Kadji, F.M.N.; Singh, G.; Kishi, T.; Uwamizu, A.; Ono, Y.; Shinjo, Y.; Ishida, S.; Arang, N.; Kawakami, K.; Gutkind, J.S.; Aoki, J.; Russell, R.B. Illuminating G-protein-coupling selectivity of GPCRs. Cell, 2019, 177(7), 1933-1947.e25.
[http://dx.doi.org/10.1016/j.cell.2019.04.044] [PMID: 31160049]
[9]
Wootten, D.; Christopoulos, A.; Marti-Solano, M.; Babu, M.M.; Sexton, P.M. Mechanisms of signalling and biased agonism in G protein-coupled receptors. Nat. Rev. Mol. Cell Biol., 2018, 19(10), 638-653.
[http://dx.doi.org/10.1038/s41580-018-0049-3] [PMID: 30104700]
[10]
Congreve, M.; de Graaf, C.; Swain, N.A.; Tate, C.G. Impact of GPCR structures on drug discovery. Cell, 2020, 181(1), 81-91.
[http://dx.doi.org/10.1016/j.cell.2020.03.003] [PMID: 32243800]
[11]
Hauser, A.S.; Attwood, M.M.; Rask-Andersen, M.; Schiöth, H.B.; Gloriam, D.E. Trends in GPCR drug discovery: New agents, targets and indications. Nat. Rev. Drug Discov., 2017, 16(12), 829-842.
[http://dx.doi.org/10.1038/nrd.2017.178] [PMID: 29075003]
[12]
Sriram, K.; Insel, P.A. G protein-coupled receptors as targets for approved drugs: How many targets and how many drugs? Mol. Pharmacol., 2018, 93(4), 251-258.
[http://dx.doi.org/10.1124/mol.117.111062] [PMID: 29298813]
[13]
Kooistra, A.J.; Mordalski, S.; Pándy-Szekeres, G.; Esguerra, M.; Mamyrbekov, A.; Munk, C.; Keserű, G.M.; Gloriam, D.E. GPCRdb in 2021: Integrating GPCR sequence, structure and function. Nucleic Acids Res., 2021, 49(D1), D335-D343.
[http://dx.doi.org/10.1093/nar/gkaa1080] [PMID: 33270898]
[14]
Paul, S.M.; Mytelka, D.S.; Dunwiddie, C.T.; Persinger, C.C.; Munos, B.H.; Lindborg, S.R.; Schacht, A.L. How to improve R&D productivity: The pharmaceutical industry’s grand challenge. Nat. Rev. Drug Discov., 2010, 9(3), 203-214.
[http://dx.doi.org/10.1038/nrd3078] [PMID: 20168317]
[15]
Veale, C.G.L. Into the fray! A beginner’s guide to medicinal chemistry. Chem. Med. Chem., 2021, 16(8), 1199-1225.
[http://dx.doi.org/10.1002/cmdc.202000929] [PMID: 33591595]
[16]
Kenakin, T. Predicting therapeutic value in the lead optimization phase of drug discovery. Nat. Rev. Drug Discov., 2003, 2(6), 429-438.
[http://dx.doi.org/10.1038/nrd1110] [PMID: 12776218]
[17]
Jorgensen, W.L. Efficient drug lead discovery and optimization. Acc. Chem. Res., 2009, 42(6), 724-733.
[http://dx.doi.org/10.1021/ar800236t] [PMID: 19317443]
[18]
Leeson, P.D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat. Rev. Drug Discov., 2007, 6(11), 881-890.
[http://dx.doi.org/10.1038/nrd2445] [PMID: 17971784]
[19]
Nassar, A.E.F.; Kamel, A.M.; Clarimont, C. Improving the decision-making process in the structural modification of drug candidates: Enhancing metabolic stability. Drug Discov. Today, 2004, 9(23), 1020-1028.
[http://dx.doi.org/10.1016/S1359-6446(04)03280-5] [PMID: 15574318]
[20]
Arnott, J.A.; Planey, S.L. The influence of lipophilicity in drug discovery and design. Expert Opin. Drug Discov., 2012, 7(10), 863-875.
[http://dx.doi.org/10.1517/17460441.2012.714363] [PMID: 22992175]
[21]
Choi, K. The structure–property relationships of clinically approved protein kinase inhibitors. Curr. Med. Chem., 2022.
[PMID: 35996243]
[22]
Wood, A.; Armour, D. The discovery of the CCR5 receptor antagonist, UK-427,857, a new agent for the treatment of HIV infection and AIDS. Prog. Med. Chem., 2005, 43, 239-271.
[http://dx.doi.org/10.1016/S0079-6468(05)43007-6] [PMID: 15850827]
[23]
Kohara, Y.; Imamiya, E.; Kubo, K.; Wada, T.; Inada, Y.; Naka, T. A new class of angiotensin II receptor antagonists with a novel acidic bioisostere. Bioorg. Med. Chem. Lett., 1995, 5(17), 1903-1908.
[http://dx.doi.org/10.1016/0960-894X(95)00319-O]
[24]
Kohara, Y.; Kubo, K.; Imamiya, E.; Wada, T.; Inada, Y.; Naka, T. Synthesis and angiotensin II receptor antagonistic activities of benzimidazole derivatives bearing acidic heterocycles as novel tetrazole bioisosteres. J. Med. Chem., 1996, 39(26), 5228-5235.
[http://dx.doi.org/10.1021/jm960547h] [PMID: 8978851]
[25]
Kurtz, T.; Kajiya, T.; Kurtz Differential pharmacology and benefit/risk of azilsartan compared to other sartans. Vasc. Health Risk Manag., 2012, 8, 133-143.
[http://dx.doi.org/10.2147/VHRM.S22595] [PMID: 22399858]
[26]
Whitman, D.B.; Cox, C.D.; Breslin, M.J.; Brashear, K.M.; Schreier, J.D.; Bogusky, M.J.; Bednar, R.A.; Lemaire, W.; Bruno, J.G.; Hartman, G.D.; Reiss, D.R.; Harrell, C.M.; Kraus, R.L.; Li, Y.; Garson, S.L.; Doran, S.M.; Prueksaritanont, T.; Li, C.; Winrow, C.J.; Koblan, K.S.; Renger, J.J.; Coleman, P.J. Discovery of a potent, CNS-penetrant orexin receptor antagonist based on an n,n-disubstituted-1,4-diazepane scaffold that promotes sleep in rats. Chem. Med. Chem., 2009, 4(7), 1069-1074.
[http://dx.doi.org/10.1002/cmdc.200900069] [PMID: 19418500]
[27]
Cox, C.D.; Breslin, M.J.; Whitman, D.B.; Schreier, J.D.; McGaughey, G.B.; Bogusky, M.J.; Roecker, A.J.; Mercer, S.P.; Bednar, R.A.; Lemaire, W.; Bruno, J.G.; Reiss, D.R.; Harrell, C.M.; Murphy, K.L.; Garson, S.L.; Doran, S.M.; Prueksaritanont, T.; Anderson, W.B.; Tang, C.; Roller, S.; Cabalu, T.D.; Cui, D.; Hartman, G.D.; Young, S.D.; Koblan, K.S.; Winrow, C.J.; Renger, J.J.; Coleman, P.J. Discovery of the dual orexin receptor antagonist [(7 R )-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1- yl][5-methyl-2-(2 H -1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia. J. Med. Chem., 2010, 53(14), 5320-5332.
[http://dx.doi.org/10.1021/jm100541c] [PMID: 20565075]
[28]
Coleman, P.J.; Cox, C.D.; Roecker, A.J. Discovery of dual orexin receptor antagonists (DORAs) for the treatment of insomnia. Curr. Top. Med. Chem., 2011, 11(6), 696-725.
[http://dx.doi.org/10.2174/1568026611109060696] [PMID: 21261591]
[29]
Inagaki, M.; Kume, M.; Tamura, Y.; Hara, S.; Goto, Y.; Haga, N.; Hasegawa, T.; Nakamura, T.; Koike, K.; Oonishi, S.; Kanemasa, T.; Kai, H. Discovery of naldemedine: A potent and orally available opioid receptor antagonist for treatment of opioid-induced adverse effects. Bioorg. Med. Chem. Lett., 2019, 29(1), 73-77.
[http://dx.doi.org/10.1016/j.bmcl.2018.11.007] [PMID: 30446313]
[30]
Inagaki, M.; Kanemasa, T.; Yokota, T. Naldemedine: Peripherally acting opioid receptor antagonist for treating opioid-induced adverse effects. Curr. Top. Med. Chem., 2020, 20(31), 2830-2842.
[http://dx.doi.org/10.2174/1568026620666200710105953] [PMID: 32648846]
[31]
Tucci, F.C.; Zhu, Y.F.; Struthers, R.S.; Guo, Z.; Gross, T.D.; Rowbottom, M.W.; Acevedo, O.; Gao, Y.; Saunders, J.; Xie, Q.; Reinhart, G.J.; Liu, X.J.; Ling, N.; Bonneville, A.K.L.; Chen, T.; Bozigian, H.; Chen, C. 3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)- 6-methylpyrimidin-2,4-dione (NBI 42902) as a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor. Design, synthesis, and in vitro and in vivo characterization. J. Med. Chem., 2005, 48(4), 1169-1178.
[http://dx.doi.org/10.1021/jm049218c] [PMID: 15715483]
[32]
Guo, Z.; Chen, Y.; Huang, C.Q.; Gross, T.D.; Pontillo, J.; Rowbottom, M.W.; Saunders, J.; Struthers, S.; Tucci, F.C.; Xie, Q.; Wade, W.; Zhu, Y.F.; Wu, D.; Chen, C. Uracils as potent antagonists of the human gonadotropin-releasing hormone receptor without atropisomers. Bioorg. Med. Chem. Lett., 2005, 15(10), 2519-2522.
[http://dx.doi.org/10.1016/j.bmcl.2005.03.057] [PMID: 15863308]
[33]
Chen, C.; Chen, Y.; Pontillo, J.; Guo, Z.; Huang, C.Q.; Wu, D.; Madan, A.; Chen, T.; Wen, J.; Xie, Q.; Tucci, F.C.; Rowbottom, M.; Zhu, Y.F.; Wade, W.; Saunders, J.; Bozigian, H.; Struthers, R.S. Potent and orally bioavailable zwitterion GnRH antagonists with low CYP3A4 inhibitory activity. Bioorg. Med. Chem. Lett., 2008, 18(11), 3301-3305.
[http://dx.doi.org/10.1016/j.bmcl.2008.04.036] [PMID: 18442910]
[34]
Chen, C.; Wu, D.; Guo, Z.; Xie, Q.; Reinhart, G.J.; Madan, A.; Wen, J.; Chen, T.; Huang, C.Q.; Chen, M.; Chen, Y.; Tucci, F.C.; Rowbottom, M.; Pontillo, J.; Zhu, Y-F.; Wade, W.; Saunders, J.; Bozigian, H.; Struthers, R.S. Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxy- phenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl- 2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor. J. Med. Chem., 2008, 51(23), 7478-7485.
[http://dx.doi.org/10.1021/jm8006454] [PMID: 19006286]
[35]
Yan, W.; Cheng, L.; Wang, W.; Wu, C.; Yang, X.; Du, X.; Ma, L.; Qi, S.; Wei, Y.; Lu, Z.; Yang, S.; Shao, Z. Structure of the human gonadotropin-releasing hormone receptor GnRH1R reveals an unusual ligand binding mode. Nat. Commun., 2020, 11(1), 5287.
[http://dx.doi.org/10.1038/s41467-020-19109-w] [PMID: 33082324]
[36]
Shore, N.D.; Saad, F.; Cookson, M.S.; George, D.J.; Saltzstein, D.R.; Tutrone, R.; Akaza, H.; Bossi, A.; van Veenhuyzen, D.F.; Selby, B.; Fan, X.; Kang, V.; Walling, J.; Tombal, B. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N. Engl. J. Med., 2020, 382(23), 2187-2196.
[http://dx.doi.org/10.1056/NEJMoa2004325] [PMID: 32469183]
[37]
Cho, N.; Harada, M.; Imaeda, T.; Imada, T.; Matsumoto, H.; Hayase, Y.; Sasaki, S.; Furuya, S.; Suzuki, N.; Okubo, S.; Ogi, K.; Endo, S.; Onda, H.; Fujino, M. Discovery of a novel, potent, and orally active nonpeptide antagonist of the human luteinizing hormone-releasing hormone (LHRH) receptor. J. Med. Chem., 1998, 41(22), 4190-4195.
[http://dx.doi.org/10.1021/jm9803673] [PMID: 9784092]
[38]
Sasaki, S.; Imaeda, T.; Hayase, Y.; Shimizu, Y.; Kasai, S.; Cho, N.; Harada, M.; Suzuki, N.; Furuya, S.; Fujino, M. A new class of potent nonpeptide luteinizing hormone-releasing hormone (LHRH) antagonists: Design and synthesis of 2-phenylimidazo[1,2-a]pyrimidin-5-ones. Bioorg. Med. Chem. Lett., 2002, 12(16), 2073-2077.
[http://dx.doi.org/10.1016/S0960-894X(02)00372-4] [PMID: 12127507]
[39]
Sasaki, S.; Cho, N.; Nara, Y.; Harada, M.; Endo, S.; Suzuki, N.; Furuya, S.; Fujino, M. Discovery of a thieno[2,3-d]pyrimidine-2,4-dione bearing a p-methoxyureidophenyl moiety at the 6-position: a highly potent and orally bioavailable non-peptide antagonist for the human luteinizing hormone-releasing hormone receptor. J. Med. Chem., 2003, 46(1), 113-124.
[http://dx.doi.org/10.1021/jm020180i] [PMID: 12502365]
[40]
Miwa, K.; Hitaka, T.; Imada, T.; Sasaki, S.; Yoshimatsu, M.; Kusaka, M.; Tanaka, A.; Nakata, D.; Furuya, S.; Endo, S.; Hamamura, K.; Kitazaki, T. Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxy- pyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d] pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor. J. Med. Chem., 2011, 54(14), 4998-5012.
[http://dx.doi.org/10.1021/jm200216q] [PMID: 21657270]
[41]
Ti, H.; Zhou, Y.; Liang, X.; Li, R.; Ding, K.; Zhao, X. Targeted treatments for chronic obstructive pulmonary disease (COPD) using low-molecular-weight drugs (LMWDs). J. Med. Chem., 2019, 62(13), 5944-5978.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01520] [PMID: 30682248]
[42]
Baur, F.; Beattie, D.; Beer, D.; Bentley, D.; Bradley, M.; Bruce, I.; Charlton, S.J.; Cuenoud, B.; Ernst, R.; Fairhurst, R.A.; Faller, B.; Farr, D.; Keller, T.; Fozard, J.R.; Fullerton, J.; Garman, S.; Hatto, J.; Hayden, C.; He, H.; Howes, C.; Janus, D.; Jiang, Z.; Lewis, C.; Loeuillet-Ritzler, F.; Moser, H.; Reilly, J.; Steward, A.; Sykes, D.; Tedaldi, L.; Trifilieff, A.; Tweed, M.; Watson, S.; Wissler, E.; Wyss, D. The identification of indacaterol as an ultralong-acting inhaled β2-adrenoceptor agonist. J. Med. Chem., 2010, 53(9), 3675-3684.
[http://dx.doi.org/10.1021/jm100068m] [PMID: 20402514]
[43]
Anderson, G.P.; Lindén, A.; Rabe, K.F. Why are long-acting beta-adrenoceptor agonists long-acting? Eur. Respir. J., 1994, 7(3), 569-578.
[http://dx.doi.org/10.1183/09031936.94.07030569] [PMID: 7912202]
[44]
Payandeh, J.; Volgraf, M. Ligand binding at the protein–lipid interface: Strategic considerations for drug design. Nat. Rev. Drug Discov., 2021, 20(9), 710-722.
[http://dx.doi.org/10.1038/s41573-021-00240-2] [PMID: 34257432]
[45]
Kikkawa, H.; Naito, K.; Ikezawa, K. Tracheal relaxing effects and β 2-selectivity of TA-2005, a newly developed bronchodilating agent, in isolated guinea pig tissues. Jpn. J. Pharmacol., 1991, 57(2), 175-185.
[http://dx.doi.org/10.1254/jjp.57.175] [PMID: 1687479]
[46]
Burkes, R.M.; Panos, R.J. Ultra long-acting β-agonists in chronic obstructive pulmonary disease. J. Exp. Pharmacol., 2020, 12, 589-602.
[http://dx.doi.org/10.2147/JEP.S259328] [PMID: 33364854]
[47]
Lainé, D.I.; McCleland, B.; Thomas, S.; Neipp, C.; Underwood, B.; Dufour, J.; Widdowson, K.L.; Palovich, M.R.; Blaney, F.E.; Foley, J.J.; Webb, E.F.; Luttmann, M.A.; Burman, M.; Belmonte, K.; Salmon, M. Discovery of novel 1-azoniabicyclo[2.2.2]octane muscarinic acetylcholine receptor antagonists. J. Med. Chem., 2009, 52(8), 2493-2505.
[http://dx.doi.org/10.1021/jm801601v] [PMID: 19317446]
[48]
Procopiou, P.A.; Barrett, V.J.; Bevan, N.J.; Biggadike, K.; Box, P.C.; Butchers, P.R.; Coe, D.M.; Conroy, R.; Emmons, A.; Ford, A.J.; Holmes, D.S.; Horsley, H.; Kerr, F.; Li-Kwai-Cheung, A.M.; Looker, B.E.; Mann, I.S.; McLay, I.M.; Morrison, V.S.; Mutch, P.J.; Smith, C.E.; Tomlin, P. Synthesis and structure-activity relationships of long-acting β2 adrenergic receptor agonists incorporating metabolic inactivation: an antedrug approach. J. Med. Chem., 2010, 53(11), 4522-4530.
[http://dx.doi.org/10.1021/jm100326d] [PMID: 20462258]
[49]
Masureel, M.; Zou, Y.; Picard, L.P.; van der Westhuizen, E.; Mahoney, J.P.; Rodrigues, J.P.G.L.M.; Mildorf, T.J.; Dror, R.O.; Shaw, D.E.; Bouvier, M.; Pardon, E.; Steyaert, J.; Sunahara, R.K.; Weis, W.I.; Zhang, C.; Kobilka, B.K. Structural insights into binding specificity, efficacy and bias of a β2AR partial agonist. Nat. Chem. Biol., 2018, 14(11), 1059-1066.
[http://dx.doi.org/10.1038/s41589-018-0145-x] [PMID: 30327561]
[50]
Manchee, G.R.; Eddershaw, P.J.; Ranshaw, L.E.; Herriott, D.; Park, G.R.; Bayliss, M.K.; Tarbit, M.H. The aliphatic oxidation of salmeterol to alpha-hydroxysalmeterol in human liver microsomes is catalyzed by CYP3A. Drug Metab. Dispos., 1996, 24(5), 555-559.
[PMID: 8723736]
[51]
Harrell, A.W.; Siederer, S.K.; Bal, J.; Patel, N.H.; Young, G.C.; Felgate, C.C.; Pearce, S.J.; Roberts, A.D.; Beaumont, C.; Emmons, A.J.; Pereira, A.I.; Kempsford, R.D. Metabolism and disposition of vilanterol, a long-acting β(2)-adrenoceptor agonist for inhalation use in humans. Drug Metab. Dispos., 2013, 41(1), 89-100.
[http://dx.doi.org/10.1124/dmd.112.048603] [PMID: 23043183]
[52]
Xing, G.; Woo, A.Y.H.; Pan, L.; Lin, B.; Cheng, M.S. Recent Advances in β2-agonists for treatment of chronic respiratory diseases and heart failure. J. Med. Chem., 2020, 63(24), 15218-15242.
[http://dx.doi.org/10.1021/acs.jmedchem.0c01195] [PMID: 33213146]
[53]
Morriello, G.J.; Wendt, H.R.; Bansal, A.; Salvo, J.D.; Feighner, S.; He, J.; Hurley, A.L.; Hreniuk, D.L.; Salituro, G.M.; Reddy, M.V.; Galloway, S.M.; McGettigan, K.K.; Laws, G.; McKnight, C.; Doss, G.A.; Tsou, N.N.; Black, R.M.; Morris, J.; Ball, R.G.; Sanfiz, A.T.; Streckfuss, E.; Struthers, M.; Edmondson, S.D. Design of a novel pyrrolidine scaffold utilized in the discovery of potent and selective human β3 adrenergic receptor agonists. Bioorg. Med. Chem. Lett., 2011, 21(6), 1865-1870.
[http://dx.doi.org/10.1016/j.bmcl.2010.12.087] [PMID: 21353541]
[54]
Moyes, C.R.; Berger, R.; Goble, S.D.; Harper, B.; Shen, D.M.; Wang, L.; Bansal, A.; Brown, P.N.; Chen, A.S.; Dingley, K.H.; Di Salvo, J.; Fitzmaurice, A.; Gichuru, L.N.; Hurley, A.L.; Jochnowitz, N.; Miller, R.R.; Mistry, S.; Nagabukuro, H.; Salituro, G.M.; Sanfiz, A.; Stevenson, A.S.; Villa, K.; Zamlynny, B.; Struthers, M.; Weber, A.E.; Edmondson, S.D. Design, synthesis, and evaluation of conformationally restricted acetanilides as potent and selective β3 adrenergic receptor agonists for the treatment of overactive bladder. J. Med. Chem., 2014, 57(4), 1437-1453.
[http://dx.doi.org/10.1021/jm4017224] [PMID: 24437735]
[55]
Edmondson, S.D.; Zhu, C.; Kar, N.F.; Di Salvo, J.; Nagabukuro, H.; Sacre-Salem, B.; Dingley, K.; Berger, R.; Goble, S.D.; Morriello, G.; Harper, B.; Moyes, C.R.; Shen, D.M.; Wang, L.; Ball, R.; Fitzmaurice, A.; Frenkl, T.; Gichuru, L.N.; Ha, S.; Hurley, A.L.; Jochnowitz, N.; Levorse, D.; Mistry, S.; Miller, R.R.; Ormes, J.; Salituro, G.M.; Sanfiz, A.; Stevenson, A.S.; Villa, K.; Zamlynny, B.; Green, S.; Struthers, M.; Weber, A.E. Discovery of vibegron: A potent and selective β3 adrenergic receptor agonist for the treatment of overactive bladder. J. Med. Chem., 2016, 59(2), 609-623.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01372] [PMID: 26709102]
[56]
Takasu, T.; Ukai, M.; Sato, S.; Matsui, T.; Nagase, I.; Maruyama, T.; Sasamata, M.; Miyata, K.; Uchida, H.; Yamaguchi, O. Effect of (R)-2-(2-aminothiazol-4-yl)-4′-{2- [(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective β3-adrenoceptor agonist, on bladder function. J. Pharmacol. Exp. Ther., 2007, 321(2), 642-647.
[http://dx.doi.org/10.1124/jpet.106.115840] [PMID: 17293563]
[57]
Takusagawa, S.; Miyashita, A.; Iwatsubo, T.; Usui, T. In vitro inhibition and induction of human cytochrome P450 enzymes by mirabegron, a potent and selective β3-adrenoceptor agonist. Xenobiotica, 2012, 42(12), 1187-1196.
[http://dx.doi.org/10.3109/00498254.2012.700140] [PMID: 22834478]
[58]
Prat, M.; Fernández, D.; Buil, M.A.; Crespo, M.I.; Casals, G.; Ferrer, M.; Tort, L.; Castro, J.; Monleón, J.M.; Gavaldà, A.; Miralpeix, M.; Ramos, I.; Doménech, T.; Vilella, D.; Antón, F.; Huerta, J.M.; Espinosa, S.; López, M.; Sentellas, S.; González, M.; Albertí, J.; Segarra, V.; Cárdenas, A.; Beleta, J.; Ryder, H. Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-[hydroxy(di-2-thienyl)acetyl] oxy-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide). J. Med. Chem., 2009, 52(16), 5076-5092.
[http://dx.doi.org/10.1021/jm900132z] [PMID: 19653626]
[59]
Woods, J.A.; Nealy, K.L.; Barrons, R.W. Aclidinium bromide: An alternative long-acting inhaled anticholinergic in the management of chronic obstructive pulmonary disease. Ann. Pharmacother., 2013, 47(7-8), 1017-1028.
[http://dx.doi.org/10.1345/aph.1S002] [PMID: 23737515]
[60]
Bang-Andersen, B.; Ruhland, T.; Jørgensen, M.; Smith, G.; Frederiksen, K.; Jensen, K.G.; Zhong, H.; Nielsen, S.M.; Hogg, S.; Mørk, A.; Stensbøl, T.B. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): A novel multimodal compound for the treatment of major depressive disorder. J. Med. Chem., 2011, 54(9), 3206-3221.
[http://dx.doi.org/10.1021/jm101459g] [PMID: 21486038]
[61]
Dhir, A. Investigational drugs for treating major depressive disorder. Expert Opin. Investig. Drugs, 2017, 26(1), 9-24.
[http://dx.doi.org/10.1080/13543784.2017.1267727] [PMID: 27960559]
[62]
Springthorpe, B.; Bailey, A.; Barton, P.; Birkinshaw, T.N.; Bonnert, R.V.; Brown, R.C.; Chapman, D.; Dixon, J.; Guile, S.D.; Humphries, R.G.; Hunt, S.F.; Ince, F.; Ingall, A.H.; Kirk, I.P.; Leeson, P.D.; Leff, P.; Lewis, R.J.; Martin, B.P.; McGinnity, D.F.; Mortimore, M.P.; Paine, S.W.; Pairaudeau, G.; Patel, A.; Rigby, A.J.; Riley, R.J.; Teobald, B.J.; Tomlinson, W.; Webborn, P.J.H.; Willis, P.A. From ATP to AZD6140: The discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis. Bioorg. Med. Chem. Lett., 2007, 17(21), 6013-6018.
[http://dx.doi.org/10.1016/j.bmcl.2007.07.057] [PMID: 17827008]
[63]
Martin, I.J.; Lewis, R.J.; Bernstein, M.A.; Beattie, I.G.; Martin, C.A.; Riley, R.J.; Springthorpe, B. Which hydroxy? Evidence for species differences in the regioselectivity of glucuronidation in rat, dog, and human in vitro systems and dog in vivo. Drug Metab. Dispos., 2006, 34(9), 1502-1507.
[http://dx.doi.org/10.1124/dmd.106.009282] [PMID: 16763016]
[64]
Kuwano, K.; Hashino, A.; Asaki, T.; Hamamoto, T.; Yamada, T.; Okubo, K.; Kuwabara, K. 2-{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304), an orally available and long-acting prostacyclin receptor agonist prodrug. J. Pharmacol. Exp. Ther., 2007, 322(3), 1181-1188.
[http://dx.doi.org/10.1124/jpet.107.124248] [PMID: 17545310]
[65]
Asaki, T.; Hamamoto, T.; Sugiyama, Y.; Kuwano, K.; Kuwabara, K. Structure–activity studies on diphenylpyra- zine derivatives: A novel class of prostacyclin receptor agonists. Bioorg. Med. Chem., 2007, 15(21), 6692-6704.
[http://dx.doi.org/10.1016/j.bmc.2007.08.010] [PMID: 17764960]
[66]
Ballatore, C.; Huryn, D.M.; Smith, A.B., III Carboxylic acid (bio)isosteres in drug design. ChemMedChem, 2013, 8(3), 385-395.
[http://dx.doi.org/10.1002/cmdc.201200585] [PMID: 23361977]
[67]
Meanwell, N.A. Synopsis of some recent tactical application of bioisosteres in drug design. J. Med. Chem., 2011, 54(8), 2529-2591.
[http://dx.doi.org/10.1021/jm1013693] [PMID: 21413808]
[68]
Nakamura, A.; Yamada, T.; Asaki, T. Synthesis and evaluation of N-acylsulfonamide and N-acylsulfonylurea prodrugs of a prostacyclin receptor agonist. Bioorg. Med. Chem., 2007, 15(24), 7720-7725.
[http://dx.doi.org/10.1016/j.bmc.2007.08.052] [PMID: 17881233]
[69]
Asaki, T.; Kuwano, K.; Morrison, K.; Gatfield, J.; Hamamoto, T.; Clozel, M. Selexipag: An oral and selective IP prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. J. Med. Chem., 2015, 58(18), 7128-7137.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00698] [PMID: 26291199]
[70]
Chun, J.; Giovannoni, G.; Hunter, S.F. Sphingosine 1-phosphate receptor modulator therapy for multiple sclerosis: Differential downstream receptor signalling and clinical profile effects. Drugs, 2021, 81(2), 207-231.
[http://dx.doi.org/10.1007/s40265-020-01431-8] [PMID: 33289881]
[71]
Bolli, M.H.; Abele, S.; Binkert, C.; Bravo, R.; Buchmann, S.; Bur, D.; Gatfield, J.; Hess, P.; Kohl, C.; Mangold, C.; Mathys, B.; Menyhart, K.; Müller, C.; Nayler, O.; Scherz, M.; Schmidt, G.; Sippel, V.; Steiner, B.; Strasser, D.; Treiber, A.; Weller, T. 2-imino-thiazolidin-4-one derivatives as potent, orally active S1P1 receptor agonists. J. Med. Chem., 2010, 53(10), 4198-4211.
[http://dx.doi.org/10.1021/jm100181s] [PMID: 20446681]
[72]
Lamb, Y.N. Ozanimod: First approval. Drugs, 2020, 80(8), 841-848.
[http://dx.doi.org/10.1007/s40265-020-01319-7] [PMID: 32385738]
[73]
Surapaneni, S.; Yerramilli, U.; Bai, A.; Dalvie, D.; Brooks, J.; Wang, X.; Selkirk, J.V.; Yan, Y.G.; Zhang, P.; Hargreaves, R.; Kumar, G.; Palmisano, M.; Tran, J.Q. Absorption, metabolism, and excretion, in vitro pharmacology, and clinical pharmacokinetics of ozanimod, a novel sphingosine 1-phosphate receptor modulator. Drug Metab. Dispos., 2021, 49(5), 405-419.
[http://dx.doi.org/10.1124/dmd.120.000220] [PMID: 33674268]
[74]
Kiuchi, M.; Adachi, K.; Kohara, T.; Minoguchi, M.; Hanano, T.; Aoki, Y.; Mishina, T.; Arita, M.; Nakao, N.; Ohtsuki, M.; Hoshino, Y.; Teshima, K.; Chiba, K.; Sasaki, S.; Fujita, T. Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols. J. Med. Chem., 2000, 43(15), 2946-2961.
[http://dx.doi.org/10.1021/jm000173z] [PMID: 10956203]
[75]
Brinkmann, V.; Billich, A.; Baumruker, T.; Heining, P.; Schmouder, R.; Francis, G.; Aradhye, S.; Burtin, P. Fingolimod (FTY720): Discovery and development of an oral drug to treat multiple sclerosis. Nat. Rev. Drug Discov., 2010, 9(11), 883-897.
[http://dx.doi.org/10.1038/nrd3248] [PMID: 21031003]
[76]
ter Haar, E.; Koth, C.M.; Abdul-Manan, N.; Swenson, L.; Coll, J.T.; Lippke, J.A.; Lepre, C.A.; Garcia-Guzman, M.; Moore, J.M. Crystal structure of the ectodomain complex of the CGRP receptor, a class-B GPCR, reveals the site of drug antagonism. Structure, 2010, 18(9), 1083-1093.
[http://dx.doi.org/10.1016/j.str.2010.05.014] [PMID: 20826335]
[77]
Paone, D.V.; Shaw, A.W.; Nguyen, D.N.; Burgey, C.S.; Deng, J.Z.; Kane, S.A.; Koblan, K.S.; Salvatore, C.A.; Mosser, S.D.; Johnston, V.K.; Wong, B.K.; Miller-Stein, C.M.; Hershey, J.C.; Graham, S.L.; Vacca, J.P.; Williams, T.M. Potent, orally bioavailable calcitonin gene-related peptide receptor antagonists for the treatment of migraine: Discovery of N -[(3 R, 6 S )-6-(2,3-Difluorophenyl)-2-oxo-1- (2,2,2-trifluoroethyl)azepan-3-yl]-4- (2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin- 1-yl)piperidine-1-carboxamide (MK-0974). J. Med. Chem., 2007, 50(23), 5564-5567.
[http://dx.doi.org/10.1021/jm070668p] [PMID: 17929795]
[78]
Dubowchik, G.M.; Conway, C.M.; Xin, A.W. Blocking the CGRP pathway for acute and preventive treatment of migraine: The evolution of success. J. Med. Chem., 2020, 63(13), 6600-6623.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01810] [PMID: 32058712]
[79]
Hargreaves, R.; Olesen, J. Calcitonin gene-related peptide modulators – the history and renaissance of a new migraine drug class. Headache, 2019, 59(6), 951-970.
[http://dx.doi.org/10.1111/head.13510] [PMID: 31020659]
[80]
Luo, G.; Chen, L.; Conway, C.M.; Denton, R.; Keavy, D.; Gulianello, M.; Huang, Y.; Kostich, W.; Lentz, K.A.; Mercer, S.E.; Schartman, R.; Signor, L.; Browning, M.; Macor, J.E.; Dubowchik, G.M. Discovery of BMS-846372, a potent and orally active human CGRP receptor antagonist for the treatment of migraine. ACS Med. Chem. Lett., 2012, 3(4), 337-341.
[http://dx.doi.org/10.1021/ml300021s] [PMID: 24900474]
[81]
Luo, G.; Chen, L.; Conway, C.M.; Denton, R.; Keavy, D.; Signor, L.; Kostich, W.; Lentz, K.A.; Santone, K.S.; Schartman, R.; Browning, M.; Tong, G.; Houston, J.G.; Dubowchik, G.M.; Macor, J.E. Discovery of (5 S, 6 S, 9 R )-5-Amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5 H -cyclohepta[ b ]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-1-yl)piperidine-1-carboxylate (BMS-927711): An oral calcitonin gene-related peptide (CGRP) antagonist in clinical trials for treating migraine. J. Med. Chem., 2012, 55(23), 10644-10651.
[http://dx.doi.org/10.1021/jm3013147] [PMID: 23153230]
[82]
Gao, Y.; Robertson, M.J.; Rahman, S.N.; Seven, A.B.; Zhang, C.; Meyerowitz, J.G.; Panova, O.; Hannan, F.M.; Thakker, R.V.; Bräuner-Osborne, H.; Mathiesen, J.M.; Skiniotis, G. Asymmetric activation of the calcium-sensing receptor homodimer. Nature, 2021, 595(7867), 455-459.
[http://dx.doi.org/10.1038/s41586-021-03691-0] [PMID: 34194040]
[83]
Wen, T.; Wang, Z.; Chen, X.; Ren, Y.; Lu, X.; Xing, Y.; Lu, J.; Chang, S.; Zhang, X.; Shen, Y.; Yang, X. Structural basis for activation and allosteric modulation of full-length calcium-sensing receptor. Sci. Adv., 2021, 7(23), eabg1483.
[http://dx.doi.org/10.1126/sciadv.abg1483] [PMID: 34088669]
[84]
Nakashima, D.; Takama, H.; Ogasawara, Y.; Kawakami, T.; Nishitoba, T.; Hoshi, S.; Uchida, E.; Tanaka, H. Effect of cinacalcet hydrochloride, a new calcimimetic agent, on the pharmacokinetics of dextromethorphan: in vitro and clinical studies. J. Clin. Pharmacol., 2007, 47(10), 1311-1319.
[http://dx.doi.org/10.1177/0091270007304103] [PMID: 17652181]
[85]
Hamano, N.; Endo, Y.; Kawata, T.; Fukagawa, M. Development of evocalcet for unmet needs among calcimimetic agents. Expert Rev. Endocrinol. Metab., 2020, 15(5), 299-310.
[http://dx.doi.org/10.1080/17446651.2020.1780911] [PMID: 32552012]
[86]
Miyazaki, H.; Ikeda, Y.; Sakurai, O.; Miyake, T.; Tsubota, R.; Okabe, J.; Kuroda, M.; Hisada, Y.; Yanagida, T.; Yoneda, H.; Tsukumo, Y.; Tokunaga, S.; Kawata, T.; Ohashi, R.; Fukuda, H.; Kojima, K.; Kannami, A.; Kifuji, T.; Sato, N.; Idei, A.; Iguchi, T.; Sakairi, T.; Moritani, Y. Discovery of evocalcet, a next-generation calcium-sensing receptor agonist for the treatment of hyperparathyroidism. Bioorg. Med. Chem. Lett., 2018, 28(11), 2055-2060.
[http://dx.doi.org/10.1016/j.bmcl.2018.04.055] [PMID: 29724589]
[87]
Kawata, T.; Tokunaga, S.; Murai, M.; Masuda, N.; Haruyama, W.; Shoukei, Y.; Hisada, Y.; Yanagida, T.; Miyazaki, H.; Wada, M.; Akizawa, T.; Fukagawa, M. A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro. PLoS One, 2018, 13(4), e0195316.
[http://dx.doi.org/10.1371/journal.pone.0195316] [PMID: 29614098]
[88]
Robarge, K.D.; Brunton, S.A.; Castanedo, G.M.; Cui, Y.; Dina, M.S.; Goldsmith, R.; Gould, S.E.; Guichert, O.; Gunzner, J.L.; Halladay, J.; Jia, W.; Khojasteh, C.; Koehler, M.F.T.; Kotkow, K.; La, H.; LaLonde, R.L.; Lau, K.; Lee, L.; Marshall, D.; Marsters, J.C., Jr; Murray, L.J.; Qian, C.; Rubin, L.L.; Salphati, L.; Stanley, M.S.; Stibbard, J.H.A.; Sutherlin, D.P.; Ubhayaker, S.; Wang, S.; Wong, S.; Xie, M. GDC-0449—A potent inhibitor of the hedgehog pathway. Bioorg. Med. Chem. Lett., 2009, 19(19), 5576-5581.
[http://dx.doi.org/10.1016/j.bmcl.2009.08.049] [PMID: 19716296]
[89]
Byrne, E.F.X.; Sircar, R.; Miller, P.S.; Hedger, G.; Luchetti, G.; Nachtergaele, S.; Tully, M.D.; Mydock-McGrane, L.; Covey, D.F.; Rambo, R.P.; Sansom, M.S.P.; Newstead, S.; Rohatgi, R.; Siebold, C. Structural basis of Smoothened regulation by its extracellular domains. Nature, 2016, 535(7613), 517-522.
[http://dx.doi.org/10.1038/nature18934] [PMID: 27437577]
[90]
Rubin, L.; Guicherit, O. M.; Price, S.; Boyd, E. A. Mediators of Hedgehog signaling pathways, compositions and uses related thereto. Patent WO2003011219A2, 2003.
[91]
Munchhof, M.J.; Li, Q.; Shavnya, A.; Borzillo, G.V.; Boyden, T.L.; Jones, C.S.; LaGreca, S.D.; Martinez-Alsina, L.; Patel, N.; Pelletier, K.; Reiter, L.A.; Robbins, M.D.; Tkalcevic, G.T. Discovery of PF-04449913, a potent and orally bioavailable inhibitor of Smoothened. ACS Med. Chem. Lett., 2012, 3(2), 106-111.
[http://dx.doi.org/10.1021/ml2002423] [PMID: 24900436]
[92]
Flock, T.; Hauser, A.S.; Lund, N.; Gloriam, D.E.; Balaji, S.; Babu, M.M. Selectivity determinants of GPCR–G-protein binding. Nature, 2017, 545(7654), 317-322.
[http://dx.doi.org/10.1038/nature22070] [PMID: 28489817]
[93]
Smith, J.S.; Lefkowitz, R.J.; Rajagopal, S. Biased signalling: From simple switches to allosteric microprocessors. Nat. Rev. Drug Discov., 2018, 17(4), 243-260.
[http://dx.doi.org/10.1038/nrd.2017.229] [PMID: 29302067]
[94]
Seyedabadi, M.; Ghahremani, M.H.; Albert, P.R. Biased signaling of G protein coupled receptors (GPCRs): Molecular determinants of GPCR/transducer selectivity and therapeutic potential. Pharmacol. Ther., 2019, 200, 148-178.
[http://dx.doi.org/10.1016/j.pharmthera.2019.05.006] [PMID: 31075355]
[95]
Tan, L.; Yan, W.; McCorvy, J.D.; Cheng, J. Biased ligands of G protein-coupled receptors (GPCRs): Structure–functional selectivity relationships (SFSRs) and therapeutic potential. J. Med. Chem., 2018, 61(22), 9841-9878.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00435] [PMID: 29939744]
[96]
Gleeson, M.P. Generation of a set of simple, interpretable ADMET rules of thumb. J. Med. Chem., 2008, 51(4), 817-834.
[http://dx.doi.org/10.1021/jm701122q] [PMID: 18232648]
[97]
Steyn, S.J.; Varma, M.V.S. Cytochrome-P450-mediated drug–drug interactions of substrate drugs: Assessing clinical risk based on molecular properties and an extended clearance classification system. Mol. Pharm., 2020, 17(8), 3024-3032.
[http://dx.doi.org/10.1021/acs.molpharmaceut.0c00444] [PMID: 32589434]
[98]
Kiani, Y.S.; Jabeen, I. Lipophilic metabolic efficiency (LipMetE) and drug efficiency indices to explore the metabolic properties of the substrates of selected cytochrome P450 isoforms. ACS Omega, 2020, 5(1), 179-188.
[http://dx.doi.org/10.1021/acsomega.9b02344] [PMID: 31956764]
[99]
Kontoyianni, M.; Liu, Z. Structure-based design in the GPCR target space. Curr. Med. Chem., 2012, 19(4), 544-556.
[http://dx.doi.org/10.2174/092986712798918824] [PMID: 22204332]
[100]
Chun, E.; Thompson, A.A.; Liu, W.; Roth, C.B.; Griffith, M.T.; Katritch, V.; Kunken, J.; Xu, F.; Cherezov, V.; Hanson, M.A.; Stevens, R.C. Fusion partner toolchest for the stabilization and crystallization of G protein-coupled receptors. Structure, 2012, 20(6), 967-976.
[http://dx.doi.org/10.1016/j.str.2012.04.010] [PMID: 22681902]
[101]
Yin, X.; Xu, H.; Hanson, M.; Liu, W. GPCR crystallization using lipidic cubic phase technique. Curr. Pharm. Biotechnol., 2014, 15(10), 971-979.
[http://dx.doi.org/10.2174/1389201015666140922110325] [PMID: 25248558]
[102]
Li, D.; Caffrey, M. Structure and functional characterization of membrane integral proteins in the lipid cubic phase. J. Mol. Biol., 2020, 432(18), 5104-5123.
[http://dx.doi.org/10.1016/j.jmb.2020.02.024] [PMID: 32113953]
[103]
García-Nafría, J.; Tate, C.G. Cryo-electron microscopy: Moving beyond X-ray crystal structures for drug receptors and drug development. Annu. Rev. Pharmacol. Toxicol., 2020, 60(1), 51-71.
[http://dx.doi.org/10.1146/annurev-pharmtox-010919-023545] [PMID: 31348870]

Rights & Permissions Print Cite
Article Metrics
87
2
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy