Unveiling dynamics of nitrogen content and selected nitrogen heterocycles in thrombin inhibitors: a ceteris paribus approach

References

• Walker CP, Royston D. Thrombin generation and its inhibition: a review of the scientific basis and mechanism of action of anticoagulant therapies. Br J Anaesth. 2002 Jun;88(6):848–863. doi: 10.1093/bja/88.6.848 PubMed PMID: 12173205.
   PubMed Web of Science ®Google Scholar
• Kong Y, Chen H, Wang YQ, et al. Direct thrombin inhibitors: patents 2002-2012 (Review). Mol Med Rep. 2014 May;9(5):1506–1514. doi: 10.3892/mmr.2014.2025 PubMed PMID: 24604304.
   PubMed Web of Science ®Google Scholar
• He LW, Dai WC, Li NG. Development of orally active thrombin inhibitors for the treatment of thrombotic disorder diseases. Molecules. [2015 Jun 15];20(6):11046–11062. doi: 10.3390/molecules200611046 PubMed PMID: 26083038; PubMed Central PMCID: PMCPMC6272601.
   PubMed Web of Science ®Google Scholar
• Lee CJ, Ansell JE. Direct thrombin inhibitors. Br J Clin Pharmacol. 2011 Oct;72(4):581–592. doi: 10.1111/j.1365-2125.2011.03916.x PubMed PMID: 21241354; PubMed Central PMCID: PMCPMC3195735.
   PubMed Web of Science ®Google Scholar
• Mackman N, Bergmeier W, Stouffer GA, et al. Therapeutic strategies for thrombosis: new targets and approaches. Nat Rev Drug Discov. 2020;19(5):333–352. doi: 10.1038/s41573-020-0061-0
   PubMed Web of Science ®Google Scholar
• Zhou Y, Yao Z, Zhu L, et al. Safety of dabigatran as an anticoagulant: a systematic review and meta-analysis. Front Pharmacol. 2021:12. doi: 10.3389/fphar.2021.626063
   Google Scholar
• di Gennaro C, Galdiero M, Scherillo G, et al. Editorial COVID-19 and Thrombosis 2023: New Waves of SARS-CoV-2 Infection, Triage Organization in Emergency department and the association of VOCs/VOI with Pulmonary Embolism. Viruses. 2022;14(11). doi: 10.3390/v14112453
   Web of Science ®Google Scholar
• Singer M, Flinterman LE, van Hylckama Vlieg A, et al. Long-term survival in a large cohort of patients with venous thrombosis: incidence and predictors. PLOS Med. 2012;9(1):e1001155. doi: 10.1371/journal.pmed.1001155
   PubMed Web of Science ®Google Scholar
• Heit JA, Silverstein MD, Mohr DN, et al. Predictors of survival after deep vein thrombosis and pulmonary embolism. Arch Internal Med. 1999;159(5). doi: 10.1001/archinte.159.5.445
   Google Scholar
• Pastori D, Cormaci VM, Marucci S, et al. A comprehensive review of risk factors for venous thromboembolism: from epidemiology to pathophysiology. Int J Mol Sci. 2023;24(4). doi: 10.3390/ijms24043169
   Web of Science ®Google Scholar
• Lutsey PL, Zakai NA. Epidemiology and prevention of venous thromboembolism. Nat Rev Cardiol. 2022;20(4):248–262. doi: 10.1038/s41569-022-00787-6
   PubMed Web of Science ®Google Scholar
• 2023 [cited 2023 Dec 25]. Available from: https://www.cdc.gov/ncbddd/dvt/data.html
   Google Scholar
• Conway EM, Mackman N, Warren RQ, et al. Understanding COVID-19-associated coagulopathy. Nat Rev Immunol. 2022;22(10):639–649. doi: 10.1038/s41577-022-00762-9
   PubMed Web of Science ®Google Scholar
• Altmann DM, Whettlock EM, Liu S, et al. The immunology of long COVID. Nat Rev Immunol. 2023;23(10):618–634. doi: 10.1038/s41577-023-00904-7
   PubMed Web of Science ®Google Scholar
• Palta S, Saroa R, Palta A. Overview of the coagulation system. Indian J Anaesth. 2014;58(5):515. doi: 10.4103/0019-5049.144643
   PubMedGoogle Scholar
• Mfuh AM, Larionov OV. Heterocyclic N-Oxides - an emerging class of therapeutic agents. Curr Med Chem. 2015;22(24):2819–2857. doi: 10.2174/0929867322666150619104007
   PubMed Web of Science ®Google Scholar
• Santana-Romo F, Lagos CF, Duarte Y, et al. Innovative Three-step microwave-promoted synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole derivatives as a potential factor Xa (FXa) inhibitors: drug design, synthesis, and biological evaluation. Molecules. 2020;25(3). doi: 10.3390/molecules25030491
   PubMed Web of Science ®Google Scholar
• Stone J, Hangge P, Albadawi H, et al. Deep vein thrombosis: pathogenesis, diagnosis, and medical management. Cardiovasc Diagn Ther. 2017;7(S3):S276–S284. doi: 10.21037/cdt.2017.09.01
   PubMedGoogle Scholar
• Huisman MV, Barco S, Cannegieter SC, et al. Pulmonary embolism. Nat Rev Dis Primers. 2018;4(1). doi: 10.1038/nrdp.2018.28
   PubMedGoogle Scholar
• Tøndel BG, Morelli VM, Hansen JB, et al. Risk factors and predictors for venous thromboembolism in people with ischemic stroke: A systematic review. J Thromb Haemost. 2022;20(10):2173–2186. doi: 10.1111/jth.15813
   PubMed Web of Science ®Google Scholar
• Dormandy K. Book review: prothrombin in enzymology, thrombosis and hemophilia. Proc R Soc Med. 2016;61(5):539–539. doi: 10.1177/003591576806100559
   Google Scholar
• Mann K, Lawson J, Ortel T, et al. A review of the therapeutic uses of thrombin. Thromb Haemost. 2017;91(5):851–860. doi: 10.1160/th03-12-0792
   Google Scholar
• Larsen JB, Hvas A-M. Thrombin: a pivotal player in Hemostasis and beyond. Semin Thromb Hemost. 2021;47(7):759–774. doi: 10.1055/s-0041-1727116
   PubMedGoogle Scholar
• Narayanan S. Multifunctional roles of thrombin. Ann Clin Lab Sci. 1999 Oct;29(4):275–280. PubMed PMID: 10528826.
   PubMed Web of Science ®Google Scholar
• Cera ED. Thrombin as procoagulant and anticoagulant. J Thromb Haemost. 2007;5:196–202. doi: 10.1111/j.1538-7836.2007.02485.x
   PubMed Web of Science ®Google Scholar
• Weisel JW, Litvinov RI. Fibrin formation, structure and properties. fibrous proteins: structures and mechanisms. Subl Biochemi. 2017;82:405–456. doi: 10.1007/978-3-319-49674-0_13
   Google Scholar
• Gupta S, Biswas A, Akhter MS, et al. Revisiting the mechanism of coagulation factor XIII activation and regulation from a structure/functional perspective. Sci Rep. 2016;6(1). doi: 10.1038/srep30105
   Google Scholar
• Wu D, Xiao J, Salsbury FR. Light chain mutation effects on the dynamics of thrombin. J Chem Inf Model. 2021;61(2):950–965. doi: 10.1021/acs.jcim.0c01303
   PubMed Web of Science ®Google Scholar
• Di Cera ET. Thrombin. Mol Aspects Med. 2008;29(4):203–254. doi: 10.1016/j.mam.2008.01.001
   PubMed Web of Science ®Google Scholar
• Downing MR, Elion J, Butkowski RJ, et al. Thrombin: structural features related to specificity1. recent progress in blood coagulation and thrombosis research. Curr Stud Hematol Blood Tranfus. 1977;44:39–53. doi: 10.1159/000402149
   Google Scholar
• Carter ISR, Vanden Hoek AL, Pryzdial ELG, et al. Thrombin A-Chain: activation remnant or allosteric effector? Thrombosis. 2010;2010:1–9. doi: 10.1155/2010/416167
   Google Scholar
• Hillisch A, Gericke KM, Allerheiligen S, et al. Design, synthesis, and pharmacological characterization of a neutral, non-prodrug thrombin inhibitor with good oral pharmacokinetics. J Med Chem. [2020 Nov 12];63(21):12574–12594. doi: 10.1021/acs.jmedchem.0c01035 PubMed PMID: 33108181.
   PubMed Web of Science ®Google Scholar
• Lee K, Park CW, Jung W-H, et al. Efficacious and orally bioavailable thrombin inhibitors based on a 2,5-thienylamidine at the P1 position: discovery of N-Carboxymethyl-d-diphenylalanyl-l-prolyl[(5-amidino-2-thienyl)methyl]amide. J Med Chem. 2003;46(17):3612–3622. doi: 10.1021/jm030025j
   PubMed Web of Science ®Google Scholar
• Nilsson M, Hämäläinen M, Ivarsson M, et al. Compounds binding to the S2−S3 pockets of thrombin. J Med Chem. 2009;52(9):2708–2715. doi: 10.1021/jm8011849
   PubMed Web of Science ®Google Scholar
• Petrera NS, Stafford AR, Leslie BA, et al. Long Range Communication between Exosites 1 and 2 modulates thrombin function. J Biol Chem. 2009;284(38):25620–25629. doi: 10.1074/jbc.M109.000042
   PubMed Web of Science ®Google Scholar
• Kovach IM, Kelley P, Eddy C, et al. Proton bridging in the interactions of thrombin with small inhibitors. Biochemistry. 2009;48(30):7296–7304. doi: 10.1021/bi900098s
   PubMed Web of Science ®Google Scholar
• Bobofchak KM, Pineda AO, Mathews FS, et al. Energetic and Structural Consequences of Perturbing Gly-193 in theOxyanion Hole of SerineProteases. J Biol Chem. 2005;280(27):25644–25650. doi: 10.1074/jbc.M503499200
   PubMedGoogle Scholar
• Fan P, Gao Y, Zheng M, et al. Recent progress and market analysis of anticoagulant drugs. J Thoracic Dis. 2018;10(3):2011–2025. doi: 10.21037/jtd.2018.03.95
   PubMed Web of Science ®Google Scholar
• Heestermans M, Poenou G, Hamzeh-Cognasse H, et al. Anticoagulants: a short history, their mechanism of action, pharmacology, and indications. Cells. 2022;11(20). doi: 10.3390/cells11203214
   PubMed Web of Science ®Google Scholar
• Goyal G, Singh R, Raj K. Anticoagulant induced spontaneous spinal epidural hematoma, conservative management or surgical intervention—A dilemma? J Acute Med. 2016;6(2):38–42. doi: 10.1016/j.jacme.2016.03.006
   Google Scholar
• De Souza RL, Short T, Warman GR, et al. Anaphylaxis with associated fibrinolysis, reversed with tranexamic acid and demonstrated by thrombelastography. Anaesth Intensive Care. 2019;32(4):580–587. doi: 10.1177/0310057x0403200419
   Google Scholar
• Masand VH, Al-Hussain S, Alzahrani AY, et al. Leveraging nitrogen occurrence in approved drugs to identify structural patterns. Expert Opin Drug Discov. 2023;19(1):111–124. doi: 10.1080/17460441.2023.2266990
   Web of Science ®Google Scholar
• Pennington LD, Moustakas DT. The necessary nitrogen atom: a versatile high-impact design element for multiparameter optimization. J Med Chem. 2017;60(9):3552–3579. doi: 10.1021/acs.jmedchem.6b01807
   PubMed Web of Science ®Google Scholar
• Bissantz C, Kuhn B, Stahl M. A medicinal chemist’s guide to molecular interactions. J Med Chem. 2010;53(14):5061–5084. doi: 10.1021/jm100112j
   PubMed Web of Science ®Google Scholar
• Vitaku E, Smith DT, Njardarson JT. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA Approved Pharmaceuticals. J Med Chem. 2014;57(24):10257–10274. doi: 10.1021/jm501100b
   PubMed Web of Science ®Google Scholar
• Aldeghi M, Malhotra S, Selwood DL, et al. Two‐ and Three‐dimensional Rings in Drugs. Chem Biol & Drug Design. 2014;83(4):450–461. doi: 10.1111/cbdd.12260
   PubMed Web of Science ®Google Scholar
• Taylor RD, MacCoss M, Lawson ADG. Rings in drugs. J Med Chem. 2014;57(14):5845–5859. doi: 10.1021/jm4017625
   PubMed Web of Science ®Google Scholar
• Gaulton A, Bellis LJ, Bento AP, et al. ChEMBL: a large-scale bioactivity database for drug discovery. Nucleic Acids Res. 2011;40(D1):D1100–D1107. doi: 10.1093/nar/gkr777
   PubMed Web of Science ®Google Scholar
• Mendez D, Gaulton A, Bento AP, et al. ChEMBL: towards direct deposition of bioassay data. Nucleic Acids Res. 2019;47(D1):D930–D940. doi: 10.1093/nar/gky1075
   PubMed Web of Science ®Google Scholar
• Gaulton A, Hersey A, Nowotka M, et al. The ChEMBL database in 2017. Nucleic Acids Res. 2017;45(D1):D945–D954. doi: 10.1093/nar/gkw1074
   PubMed Web of Science ®Google Scholar
• Ambure P, Mnds C. Importance of data curation in qsar studies especially while modeling large-size datasets. Ecotoxicological QSARs. Meth Pharmacol Toxicol. 2020:97–109. doi: 10.1007/978-1-0716-0150-1_5
   Google Scholar
• Alves VM, Auerbach SS, Kleinstreuer N, et al. Curated Data in — Trustworthy in silico models out: the impact of data Quality on the reliability of artificial intelligence models as alternatives to animal testing. Altern To Lab Anim. 2021;49(3):73–82. doi: 10.1177/02611929211029635
   PubMed Web of Science ®Google Scholar
• Fourches D, Muratov E, Trust TA, et al. Trust, but verify: on the importance of chemical structure curation in cheminformatics and QSAR Modeling Research. J Chem Inf Model. 2010;50(7):1189–1204. doi: 10.1021/ci100176x
   PubMed Web of Science ®Google Scholar
• Masand VH, Rastija V. PyDescriptor: a new PyMOL plugin for calculating thousands of easily understandable molecular descriptors. Chemometr Intell Lab Syst. 2017;169:12–18. doi: 10.1016/j.chemolab.2017.08.003
   Web of Science ®Google Scholar
• Sun D, Gao W, Hu H, et al. Why 90% of clinical drug development fails and how to improve it? Acta Pharm Sin B. 2022;12(7):3049–3062. doi: 10.1016/j.apsb.2022.02.002
   PubMed Web of Science ®Google Scholar
• Ertl P, Altmann E, McKenna JM. The most common functional groups in bioactive molecules and how their popularity has evolved over time. J Med Chem. 2020;63(15):8408–8418. doi: 10.1021/acs.jmedchem.0c00754
   PubMed Web of Science ®Google Scholar
• Pennington LD, Collier PN, Comer E. Harnessing the necessary nitrogen atom in chemical biology and drug discovery. Med Chem Res. 2023;32(7):1278–1293. doi: 10.1007/s00044-023-03073-3
   Web of Science ®Google Scholar
• Ertl P, Altmann E, Racine S. The most common linkers in bioactive molecules and their bioisosteric replacement network. Bioorg Med Chem. 2023;81. doi: 10.1016/j.bmc.2023.117194
   Web of Science ®Google Scholar
• Kerns EH, Di L. Drug-like properties : concepts, structure design and methods : from ADME to toxicity optimization. Amsterdam; Boston: Academic Press; 2008.
   Google Scholar
• Silverman RB, Holladay MW. The organic chemistry of drug design and drug action. Third edition ed. Amsterdam; Boston: Elsevier/AP, Academic Press, is an imprint of Elsevier; 2014.
   Google Scholar
• Lovering F, Bikker J, Humblet C. Escape from Flatland: increasing saturation as an approach to improving clinical success. J Med Chem. 2009;52(21):6752–6756. doi: 10.1021/jm901241e
   PubMed Web of Science ®Google Scholar
• Ritchie TJ, Macdonald SJF, Peace S, et al. The developability of heteroaromatic and heteroaliphatic rings – do some have a better pedigree as potential drug molecules than others? Med Chem Commun. 2012;3(9):1062. doi: 10.1039/c2md20111a
   Google Scholar
• Panday SK. Advances in the chemistry of proline and its derivatives: an excellent amino acid with versatile applications in asymmetric synthesis. Tetrahedron: Asymmetry. 2011;22(20–22):1817–1847. doi: 10.1016/j.tetasy.2011.09.013
   Google Scholar
• Bach TMH, Takagi H. Properties, metabolisms, and applications of l-proline analogues. Appl Microbiol Biotechnol. 2013;97(15):6623–6634. doi: 10.1007/s00253-013-5022-7
   PubMed Web of Science ®Google Scholar
• Thorat BR, Mali SN, Wavhal SS, et al. L-Proline: a versatile organo-catalyst in organic chemistry. Comb Chem & High Throughput Screening. 2023;26(6):1108–1140. doi: 10.2174/1386207325666220720105845
   PubMed Web of Science ®Google Scholar
• Li Petri G, Raimondi MV, Spanò V, et al. Pyrrolidine in drug discovery: a versatile scaffold for novel biologically active compounds. Top In Curr Chem. 2021;379(5). doi: 10.1007/s41061-021-00347-5
   Web of Science ®Google Scholar
• Kunitski M, Riehn C, Matylitsky VV, et al. Pseudorotation in pyrrolidine: rotational coherence spectroscopy and ab initio calculations of a large amplitude intramolecular motion. Phys Chem Chem Phys. 2010;12(1):72–81. doi: 10.1039/b917362e
   PubMed Web of Science ®Google Scholar
• Schreuder H, Matter H. Serine proteinases from the blood coagulation cascade. Struct Biol Drug Discov. 2020:395–422. doi: 10.1002/9781118681121.ch17
   Google Scholar
• Hanessian S, Tremblay M, Petersen JFW. TheN-Acyloxyiminium Ion aza-prins route to octahydroindoles: total synthesis and structural confirmation of the antithrombotic marine natural product oscillarin. J Am Chem Soc. 2004;126(19):6064–6071. doi: 10.1021/ja030669g
   PubMed Web of Science ®Google Scholar
• Brecher AS, Murrey SJ, Gray KD, et al. Anticoagulant Activity of Captopril. J Cardiovasc Pharmacol. 2008;51(1):99–105. doi: 10.1097/FJC.0b013e31815d1d3e
   PubMed Web of Science ®Google Scholar
• Morrissette MM, Stauffer KJ, Williams PD, et al. Low molecular weight thrombin inhibitors with excellent potency, metabolic stability, and oral bioavailability. Bioorg & Med Chem Lett. 2004;14(16):4161–4164. doi: 10.1016/j.bmcl.2004.06.030
   PubMed Web of Science ®Google Scholar
• Blizzard TA, Singh S, Patil B, et al. Heterocyclic core analogs of a direct thrombin inhibitor. Bioorg & Med Chem Lett. 2014;24(4):1111–1115. doi: 10.1016/j.bmcl.2014.01.002
   PubMed Web of Science ®Google Scholar
• Hamada Y. Role of pyridines in medicinal chemistry and design of bace1 inhibitors possessing a pyridine scaffold. Pyridine. 2018. doi: 10.5772/intechopen.74719
   Google Scholar
• Islam MB, Islam MI, Nath N, et al. Recent advances in pyridine scaffold: focus on chemistry, synthesis, and antibacterial activities. Bio Med Res Int. 2023;2023:1–15. doi: 10.1155/2023/9967591
   Google Scholar
• Zhao L, Song X, Gong C, et al. Reply to Brzeski and Jordan: Potential pyridine tautomers that can form stable dipole-bound anions. Proc Nat Acad Sci. 2022;119(38). doi: 10.1073/pnas.2212433119
   Google Scholar
• Sharif S, Huot MC, Tolstoy PM, et al. 15N Nuclear magnetic resonance studies of acid−base properties of pyridoxal-5‘-Phosphate Aldimines in Aqueous Solution. J Phys Chem B. 2007;111(15):3869–3876. doi: 10.1021/jp067334g
   PubMed Web of Science ®Google Scholar
• Ling Y, Hao ZY, Liang D, et al. The expanding role of pyridine and dihydropyridine scaffolds in drug design. Drug Des Devel Ther. 2021;15:4289–4338. doi: 10.2147/DDDT.S329547 PubMed PMID: 34675489; PubMed Central PMCID: PMCPMC8520849.
   PubMed Web of Science ®Google Scholar
• Stauffer KJ, Williams PD, Selnick HG, et al. 9-hydroxyazafluorenes and their use in thrombin inhibitors. J Med Chem. 2005;48(7):2282–2293. doi: 10.1021/jm049423s
   PubMed Web of Science ®Google Scholar
• Rautio J, Meanwell NA, Di L, et al. The expanding role of prodrugs in contemporary drug design and development. Nat Rev Drug Discov. 2018;17(8):559–587. doi: 10.1038/nrd.2018.46
   PubMed Web of Science ®Google Scholar
• Beno BR, Yeung K-S, Bartberger MD, et al. A survey of the role of noncovalent sulfur interactions in drug design. J Med Chem. 2015;58(11):4383–4438. doi: 10.1021/jm501853m
   PubMed Web of Science ®Google Scholar
• Cascioferro S, Parrino B, Carbone D, et al. Thiazoles, their benzofused systems, and thiazolidinone derivatives: versatile and promising tools to combat antibiotic resistance. J Med Chem. 2020;63(15):7923–7956. doi: 10.1021/acs.jmedchem.9b01245
   PubMed Web of Science ®Google Scholar
• Adang AEP, de Man APA, Vogel GMT, et al. Unique overlap in the prerequisites for thrombin inhibition and oral bioavailability resulting in potent oral antithrombotics. J Med Chem. 2002;45(20):4419–4432. doi: 10.1021/jm011110z
   PubMed Web of Science ®Google Scholar
• Green H, Day AR. The tautomeric character of the imidazole ring. J Am Chem Soc. 2002;64(5):1167–1173. doi: 10.1021/ja01257a047
   Google Scholar
• Tolomeu HV, Fraga CAM. Imidazole: synthesis, functionalization and physicochemical properties of a privileged structure in medicinal chemistry. Molecules. 2023;28(2). doi: 10.3390/molecules28020838
   PubMed Web of Science ®Google Scholar
• Jaladanki CK, Taxak N, Varikoti RA, et al. Toxicity originating from thiophene containing drugs: exploring the mechanism using quantum chemical methods. Chem Res Toxicol. 2015;28(12):2364–2376. doi: 10.1021/acs.chemrestox.5b00364
   PubMed Web of Science ®Google Scholar
• Dalvie DK, Kalgutkar AS, Khojasteh-Bakht SC, et al. Biotransformation reactions of five-membered aromatic heterocyclic rings. Chem Res Toxicol. 2002;15(3):269–299. doi: 10.1021/tx015574b
   PubMed Web of Science ®Google Scholar
• Huang H, Li H, Yang S, et al. Potent and selective double-headed thiophene-2-carboximidamide inhibitors of neuronal nitric oxide synthase for the treatment of melanoma. J Med Chem. 2014;57(3):686–700. doi: 10.1021/jm401252e
   PubMed Web of Science ®Google Scholar