Homologation: A Versatile Molecular Modification Strategy to Drug Discovery

Author(s): Lídia M. Lima*, Marina A. Alves, Daniel N. do Amaral

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 19 , 2019


DOI : 10.2174/1568026619666190808145235

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Graphical Abstract:


Abstract:

Homologation is a concept introduced by Gerhard in 1853 to describe a homologous series in organic chemistry. Since then, the concept has been adapted and used in medicinal chemistry as one of the most important strategies for molecular modification. The homologation types, their influence on physico-chemical properties and molecular conformation are presented and discussed. Its application in lead-identification and lead optimization steps, as well as its impact on pharmacodynamics/pharmacokinetic properties and on protein structure is highlighted from selected examples.

• Homologation: definition and types

• Homologous series in nature

• Comparative physico-chemical and conformational properties

• Application in lead-identification and lead-optimization

• Impact on pharmacodynamic property

• Impact on pharmacokinetic property

• Impact on protein structure

• Concluding remarks

• Acknowledgment

• References

Keywords: Homologation, Homologous, Molecular modification strategy, Drug discovery, Lead optimization, Organic compounds.

[1]
Gerhardt, C. Principles of serial classification. In: .Treat of Organic Chemistry; Firmin Didot Frères: Paris, 1853.
[2]
Lima, L.M.; Barreiro, E.J. Bioisosterism: A useful strategy for molecular modification and drug design. Curr. Med. Chem., 2005, 12(1), 23-49.
[http://dx.doi.org/10.2174/0929867053363540] [PMID: 15638729]
[3]
Graham, P.L. An introduction to medicinal chemistry. Oxford University Press, United States, 2009.
[4]
Bruun, J.H.; Hicks-Bruun, M.M. RP239-IE isolation of the isomers of hexane from petroleum. (Available at: . https://nvlpubs. nist.gov/nistpubs/jres/5/jresv5n4p933_a2b.pdf
[5]
Rustan, A.C.; Drevon, C.A. Fatty acids: Structures and Properties. In:Encyclopedia Life Science; John Wiley & Sons: New York, 2005, pp. 1-7.
[http://dx.doi.org/10.1038/npg.els.0000715]
[6]
Hammett, L.P. The effect of structure upon the reactions of organic compounds. benzene derivatives. J. Am. Chem. Soc., 1937, 59, 96-103.
[http://dx.doi.org/10.1021/ja01280a022]
[7]
Arnott, J. Lipophilicity indices for drug development. J. Appl. Biopharm. Pharmacokinect., 2013, 1, 31-36.
[http://dx.doi.org/10.14205/2309-4435.2013.01.01.6]
[8]
Lipinski, C.A. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1(4), 337-341.
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID: 24981612]
[9]
McAuliffe, C.; Habra, L. Solubility in water of paraffin, cycloparaffin, olefin, acetylene, cycloolefin, and aromatic hydrocarbons1. J. Phys. Chem., 1966, 70, 1267-1275.
[http://dx.doi.org/10.1021/j100876a049]
[10]
Chen, D.; Soh, C.K.; Goh, W.H.; Wang, H. Design, synthesis, and preclinical evaluation of fused pyrimidine-based hydroxamates for the treatment of hepatocellular carcinoma. J. Med. Chem., 2018, 61(4), 1552-1575.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01465] [PMID: 29360358]
[11]
Guo, T.; Dätwyler, P.; Demina, E.; Richards, M.R.; Ge, P.; Zou, C.; Zheng, R.; Fougerat, A.; Pshezhetsky, A.V.; Ernst, B.; Cairo, C.W. Selective inhibitors of human neuraminidase 3. J. Med. Chem., 2018, 61(5), 1990-2008.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01574] [PMID: 29425031]
[12]
Liu, Y.; Ji, L.; Eno, M.; Kudalkar, S.; Li, A-L.; Schimpgen, M.; Benchama, O.; Morales, P.; Xu, S.; Hurst, D.; Wu, S.; Mohammad, K.A.; Wood, J.T.; Zvonok, N.; Papahatjis, D.P.; Zhou, H.; Honrao, C.; Mackie, K.; Reggio, P.; Hohmann, A.G.; Marnett, L.J.; Makriyannis, A.; Nikas, S.P. (R)- N-(1-Methyl-2-hydroxyethyl)-13-(S)-methyl-arachidonamide (AMG315): A novel chiral potent endocannabinoid ligand with stability to metabolizing enzymes. J. Med. Chem., 2018, 61(19), 8639-8657.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00611] [PMID: 30196704]
[13]
Kang, D.; Zhang, H.; Wang, Z.; Zhao, T.; Ginex, T.; Luque, F.J.; Yang, Y.; Wu, G.; Feng, D.; Wei, F.; Zhang, J.; De Clercq, E.; Pannecouque, C.; Chen, C.H.; Lee, K-H.; Murugan, N.A.; Steitz, T.A.; Zhan, P.; Liu, X. Identification of dihydrofuro[3,4- d]pyrimidine derivatives as novel HIV-1 non-nucleoside reverse transcriptase inhibitors with promising antiviral activities and desirable physicochemical properties. J. Med. Chem., 2019, 62(3), 1484-1501.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01656] [PMID: 30624934]
[14]
Rew, Y.; Du, X.; Eksterowicz, J.; Zhou, H.; Jahchan, N.; Zhu, L.; Yan, X.; Kawai, H.; McGee, L.R.; Medina, J.C.; Huang, T.; Chen, C.; Zavorotinskaya, T.; Sutimantanapi, D.; Waszczuk, J.; Jackson, E.; Huang, E.; Ye, Q.; Fantin, V.R.; Sun, D. Discovery of a potent and selective steroidal glucocorticoid receptor antagonist (ORIC-101). J. Med. Chem., 2018, 61(17), 7767-7784.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00743] [PMID: 30091920]
[15]
Chowdhury, S.; Owens, K.N.; Herr, R.J.; Jiang, Q.; Chen, X.; Johnson, G.; Groppi, V.E.; Raible, D.W.; Rubel, E.W.; Simon, J.A. Phenotypic optimization of urea-thiophene carboxamides to yield potent, well tolerated, and orally active protective agents against aminoglycoside-induced hearing loss. J. Med. Chem., 2018, 61(1), 84-97.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00932] [PMID: 28992413]
[16]
Peese, K.M.; Allard, C.W.; Connolly, T.; Johnson, B.L.; Li, C.; Patel, M.; Sorensen, M.E.; Walker, M.A.; Meanwell, N.A.; McAuliffe, B.; Minassian, B.; Krystal, M.; Parker, D.D.; Lewis, H.A.; Kish, K.; Zhang, P.; Nolte, R.T.; Simmermacher, J.; Jenkins, S.; Cianci, C.; Naidu, B.N. 5,6,7,8-Tetrahydro-1,6-naphthyridine derivatives as potent HIV-1-integrase-allosteric-site inhibitors. J. Med. Chem., 2019, 62(3), 1348-1361.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01473] [PMID: 30609350]
[17]
Daina, A.; Giuliano, C.; Pietra, C.; Wang, J.; Chi, Y.; Zou, Z.; Li, F.; Yan, Z.; Zhou, Y.; Guainazzi, A.; Garcia Rubio, S.; Zoete, V. Rational design, synthesis, and pharmacological characterization of novel ghrelin receptor inverse agonists as potential treatment against obesity-related metabolic diseases. J. Med. Chem., 2018, 61(24), 11039-11060.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00794] [PMID: 30265805]
[18]
Del Bello, F.; Bonifazi, A.; Giorgioni, G.; Cifani, C.; Micioni Di Bonaventura, M.V.; Petrelli, R.; Piergentili, A.; Fontana, S.; Mammoli, V.; Yano, H.; Matucci, R.; Vistoli, G.; Quaglia, W. 1-[3-(4-Butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1) as a model for the rational design of a novel class of brain penetrant ligands with high affinity and selectivity for dopamine D4 receptor. J. Med. Chem., 2018, 61(8), 3712-3725.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00265] [PMID: 29589445]
[19]
Bosma, R.; Mocking, T.A.M.; Leurs, R.; Vischer, H.F. Ligand-Binding Kinetics on Histamine Receptors; Humana Press: New York, NY, 2017, pp. 115-155.
[20]
Xu, J.; Zhang, X.; Qian, Q.; Wang, Y.; Dong, H.; Li, N.; Qian, Y.; Jin, W. Histamine upregulates the expression of histamine receptors and increases the neuroprotective effect of astrocytes. J. Neuroinflamm., 2018, 151(1), 41.
[http://dx.doi.org/10.1186/s12974-018-1068-x]
[21]
Hudkins, R.L.; Raddatz, R.; Tao, M.; Mathiasen, J.R.; Aimone, L.D.; Becknell, N.C.; Prouty, C.P.; Knutsen, L.J.S.; Yazdanian, M.; Moachon, G.; Ator, M.A.; Mallamo, J.P.; Marino, M.J.; Bacon, E.R.; Williams, M. Discovery and characterization of 6-4-[3-(R)-2-Methylpyrrolidin-1-yl)propoxy]phenyl-2H-pyridazin-3-one (CEP-26401, Irdabisant): A potent, selective histamine h3 receptor inverse Agonist. J. Med. Chem., 2011, 54, 4781-4792.
[http://dx.doi.org/10.1021/jm200401v] [PMID: 21634396]
[22]
King, H.O.; Brend, T.; Payne, H.L.; Wright, A.; Ward, T.A.; Patel, K.; Egnuni, T.; Stead, L.F.; Patel, A.; Wurdak, H.; Short, S.C. RAD51 Is a selective DNA Repair Target to Radiosensitize Glioma Stem Cells. Stem Cell Reports, 2017, 8(1), 125-139.
[http://dx.doi.org/10.1016/j.stemcr.2016.12.005] [PMID: 28076755]
[23]
Helleday, T. Homologous recombination in cancer development, treatment and development of drug resistance. Carcinogenesis, 2010, 31(6), 955-960.
[http://dx.doi.org/10.1093/carcin/bgq064] [PMID: 20351092]
[24]
Ward, A.; Dong, L.; Harris, J.M.; Khanna, K.K.; Al-Ejeh, F.; Fairlie, D.P.; Wiegmans, A.P.; Liu, L. Quinazolinone derivatives as inhibitors of homologous recombinase RAD51. Bioorg. Med. Chem. Lett., 2017, 27(14), 3096-3100.
[http://dx.doi.org/10.1016/j.bmcl.2017.05.039] [PMID: 28545975]
[25]
Chung, S.; Wendeler, M.; Rausch, J.W.; Beilhartz, G.; Gotte, M.; O’Keefe, B.R.; Bermingham, A.; Beutler, J.A.; Liu, S.; Zhuang, X.; Le Grice, S.F.J. Structure-activity analysis of vinylogous urea inhibitors of human immunodeficiency virus-encoded ribonuclease H. Antimicrob. Agents Chemother., 2010, 54(9), 3913-3921.
[http://dx.doi.org/10.1128/AAC.00434-10] [PMID: 20547794]
[26]
Dosa, P.I.; Ward, T.; Walters, M.A.; Kim, S.W. Synthesis of novel analogs of cabergoline: improving cardiovascular safety by removing 5-HT2B receptor agonism. ACS Med. Chem. Lett., 2013, 4(2), 254-258.
[http://dx.doi.org/10.1021/ml3003814] [PMID: 23606928]
[27]
Jordan, C.G.; Jordan, M. How an increase in the carbon chain length of the ester moiety affects the stability of a homologous series of oxprenolol esters in the presence of biological enzymes. J. Pharm. Sci., 1998, 87(7), 880-885.
[http://dx.doi.org/10.1021/js970280p] [PMID: 9649358]
[28]
Wang, H-L.; Andrews, K.L.; Booker, S.K.; Canon, J.; Cee, V.J.; Chavez, F., Jr; Chen, Y.; Eastwood, H.; Guerrero, N.; Herberich, B.; Hickman, D.; Lanman, B.A.; Laszlo, J., III; Lee, M.R.; Lipford, J.R.; Mattson, B.; Mohr, C.; Nguyen, Y.; Norman, M.H.; Pettus, L.H.; Powers, D.; Reed, A.B.; Rex, K.; Sastri, C.; Tamayo, N.; Wang, P.; Winston, J.T.; Wu, B.; Wu, Q.; Wu, T.; Wurz, R.P.; Xu, Y.; Zhou, Y.; Tasker, A.S. Discovery of (R)-8-(6-Methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4- b]pyrrol-2-yl)-3-(1-methylcyclo-propyl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3 H)-one, a Potent and Selective Pim-1/2 Kinase Inhibitor for Hematological Malignancies. J. Med. Chem., 2019, 62(3), 1523-1540.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01733] [PMID: 30624936]
[29]
Ratni, H.; Ebeling, M.; Baird, J.; Bendels, S.; Bylund, J.; Chen, K.S.; Denk, N.; Feng, Z.; Green, L.; Guerard, M.; Jablonski, P.; Jacobsen, B.; Khwaja, O.; Kletzl, H.; Ko, C-P.; Kustermann, S.; Marquet, A.; Metzger, F.; Mueller, B.; Naryshkin, N.A.; Paushkin, S.V.; Pinard, E.; Poirier, A.; Reutlinger, M.; Weetall, M.; Zeller, A.; Zhao, X.; Mueller, L. discovery of risdiplam, a selective survival of motor neuron-2 (SMN2) gene splicing modifier for the treatment of spinal muscular atrophy (SMA). J. Med. Chem., 2018, 61(15), 6501-6517.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00741] [PMID: 30044619]
[30]
Bachovchin, K.A.; Sharma, A.; Bag, S.; Klug, D.M.; Schneider, K.M.; Singh, B.; Jalani, H.B.; Buskes, M.J.; Mehta, N.; Tanghe, S.; Momper, J.D.; Sciotti, R.J.; Rodriguez, A.; Mensa-Wilmot, K.; Pollastri, M.P.; Ferrins, L. Improvement of aqueous solubility of lapatinib-derived analogues: Identification of a quinolinimine lead for human african trypanosomiasis drug development. J. Med. Chem., 2019, 62(2), 665-687.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01365] [PMID: 30565932]
[31]
Hammill, J.T.; Bhasin, D.; Scott, D.C.; Min, J.; Chen, Y.; Lu, Y.; Yang, L.; Kim, H.S.; Connelly, M.C.; Hammill, C.; Holbrook, G.; Jeffries, C.; Singh, B.; Schulman, B.A.; Guy, R.K. Discovery of an orally bioavailable inhibitor of defective in cullin neddylation 1 (DCN1)-mediated cullin neddylation. J. Med. Chem., 2018, 61(7), 2694-2706.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01282] [PMID: 29547693]
[32]
Gierse, J.K.; McDonald, J.J.; Hauser, S.D.; Rangwala, S.H.; Koboldt, C.M.; Seibert, K. A single amino acid difference between cyclooxygenase-1 (COX-1) and -2 (COX-2) reverses the selectivity of COX-2 specific inhibitors. J. Biol. Chem., 1996, 271(26), 15810-15814.
[http://dx.doi.org/10.1074/jbc.271.26.15810] [PMID: 8663121]
[33]
Park, H.; Lee, S. Free energy perturbation approach to the critical assessment of selective cyclooxygenase-2 inhibitors. J. Comput. Aided Mol. Des., 2005, 19(1), 17-31.
[http://dx.doi.org/10.1007/s10822-005-0098-5] [PMID: 16059664]
[34]
Iu, Y.P.H.; Helander, S.; Kahlin, A.Z.; Cheng, C.W.; Shek, C.C.; Leung, M.H.; Wallner, B.; Mårtensson, L.G.; Appell, M.L. One amino acid makes a difference-Characterization of a new TPMT allele and the influence of SAM on TPMT stability. Sci. Rep., 2017, 7, 46428.
[http://dx.doi.org/10.1038/srep46428] [PMID: 28462921]
[35]
Debler, E.W.; Jain, K.; Warmack, R.A.; Feng, Y.; Clarke, S.G.; Blobel, G.; Stavropoulos, P. A glutamate/aspartate switch controls product specificity in a protein arginine methyltransferase. Proc. Natl. Acad. Sci. USA, 2016, 113(8), 2068-2073.
[http://dx.doi.org/10.1073/pnas.1525783113] [PMID: 26858449]
[36]
Jung, S.M.; Le, D.T.; Yoon, S.S.; Yoon, M.Y.; Kim, Y.T.; Choi, J.D. Amino acid residues conferring herbicide resistance in tobacco acetohydroxy acid synthase. Biochem. J., 2004, 383(Pt 1), 53-61.
[http://dx.doi.org/10.1042/BJ20040720] [PMID: 15214847]


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Article Details

VOLUME: 19
ISSUE: 19
Year: 2019
Published on: 20 October, 2019
Page: [1734 - 1750]
Pages: 17
DOI: 10.2174/1568026619666190808145235
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