Abstract
Bicyclic heteroaromatic motifs with hydrogen bond donor–acceptor hinge binder motifs are frequently used as ATP-mimetic kinase inhibitors. Althought the thieno[2,3-c]pyridine scaffold also meets these criteria its use was limited so far by the availability of synthetic building blocks. Inspired by two X-ray structures of kinase bound thieno[2,3-c]pyridines we prepared a diverse collection of simple thieno[2,3-c]pyridine derivatives that could serve as starting points for future drug discovery programs. In our search for inhibitors of the GRK2 kinase we also identified a hit compound bearing the thieno[2,3-c]pyridine moiety. Following a structure-driven optimization process a collection of potent and highly ligand efficient inhibitors were prepared and characterized, which could form the basis of a future drug discovery program.
Graphical abstract
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Litvinov VP, Dotsenko VV, Krivokolysko SG (2007) The Chemistry of Thienopyridines. In: Katritzky AR (ed) Advances in Heterocyclic Chemistry, vol 93. Academic Press, Cambridge, p 117
Cohen P, Cross D, Jänne PA (2021) Nat Rev Drug Discov 20:551
Koehler MFT, Bergeron P, Blackwood EM, Bowman K, Clark KR, Firestein R, Kiefer JR, Maskos K, McCleland ML, Orren L, Salphati L, Schmidt S, Schneidero EV, Wu J, Beresini MH (2016) ACS Med Chem Lett 7:223
Buckmelter AJ, Ren L, Laird ER, Rast B, Miknis G, Wenglowsky S, Schlachter S, Welch M, Tarlton E, Grina J, Lyssikatos J, Brandhuber BJ, Morales T, Randolph N, Vigers G, Martinson M, Callejo M (2011) Bioorg Med Chem Lett 21:1248
Cusack K, Allen H, Bischoff A, Clabbers A, Dixon R, Fix-Stenzel S, Friedman M, Gaumont Y, Dawn G, Gordon T, Grongsaard P, Janssen B, Jia Y, Moskey M, Quinn C, Salmeron A, Thomas C, Wallace G, Wishart N, Yu Z (2009) Bioorg Med Chem Lett 19:1722
Cusack K, Salmeron-Garcia JA, Gordon TD, Barberis CE, Allen HJ, Bischoff AK, Ericsson AM, Friedman MM, George DM, Roth GP, Talanian RV, Thomas C, Wallace GA, Wishart N, Yu Z (2005) Kinase inhibitors as therapeutic agents. Chem Abstr 144:22906 (WO 2005110410, Nov 24, 2005; (2005))
Koehler MFT, Bergeron P, Blackwood EM, Bowman K, Clark K, Firestein R, Kiefer JR, Maskoso K, McCleland ML, Orren L, Salphati L, Schmidt S, Schneider EV, Wu J, Beresin MH (2016) ACS Med Chem Lett 7:2232
Zhu GD, Arendsen DL, Gunawardana IL, Boyd SA, Stewart AO, Fry DG, Cool BL, Kifle L, Schaefer V, Meuth J, Marsh KC, Kempf-Grote AJ, Kilgannon P, Michael Gallatin W, Okasinski GF (2001) J Med Chem 44:3469
Zhu G-D, Gunawardana IW, Boyd SA, Melche LM (2008) J Heterocycl Chem 45:91
Zhu G-D, Schaefer V, Boyd SA, Okasinski GF (2002) J Org Chem 67:943
George D, Friedman M, Allen H, Argiriadi M, Barberis C, Bischoff A, Clabbers A, Cusack K, Dixon R, Fix-Stenzel S, Gordon T, Janssen B, Jia Y, Moskey M, Quinn C, Salmeron JA, Wishart N, Woller K, Yu Z (2008) Bioorg Med Chem Lett 18:4952
Hong YR, Lee MJK, Kim JM, Park S, Lee W, Choi J-R, Ro S, Cho JM, Masamune H, Elliott GT (2011) Pyridine derivatives for treating HIF-related disorders. Chem Abstr 154:580291 (WO 2011056725, May 12, 2011; (2011))
Cusack K, Salmeron-Garcia J-A, Gordon TD, Barberis CE, Allen HJ, Bischoff AK, Ericsson AM, Friedman MM, George DM, Roth GP, Talanian RV, Thomas C, Wallace GA, Wishart N, Yu Z (2005) Preparation of fused heterocycle kinase inhibitors for treatment of protein tyrosine kinase-related diseases. Chem Abstr 144:22906 (WO 2005110410, Nov 24, 2005; (2005))
Wang Z, Li N (2019) Heterocyclic compounds as inhibitors of fibroblast growth factor receptor and their preparation. Chem Abstr 170:573070 (WO 2019080878, May 2, 2019; (2019))
Iddon B, Suschitzky H, Thompson AW, Wakefield BJ, Wright DJ (1978) J Chem Res S 5:174
Yogo T, Hara R, Fukuda K (2011) Preparation of heterocyclic compounds as glucagon antagonists. Chem Abstr 154:310634 (WO 2011027849, Mar 10, 2011; (2011))
Meyer MD, Altenbach RJ, Basha F, Carroll WA, Drizin I, Kerwin JF, Wendt MD, Haight AR, Zhang W (1998) Preparation of benzopyranopyrrole and benzopyranopyridine as α-1 adrenergic antagonists. Chem Abstr 129:67797 (WO 9824791, Jun 11, 1998; (1998))
Stewart AO, Boyd SA, Arendsen DL, Bhatia P, Condroski KR, Freeman JC, Gunawardana IW, Zhu G-D, Lartey K, McCarty CM, Mort NA, Patel MV, Staeger MA, Stout DM (1999) Preparation of thienopyrimidinecarboxamides and analogs as cell adhesion-inhibiting antiinflammatory compounds. Chem Abstr 132:22956 (WO 9962908, Dec 9, 1999; (1999))
Arendsen DL, Bhatia P, Boyd SA, Condroski KR, Freeman JC, Gunawardana IW, Lartey K, McCarty CM, Mort NA, Patel MV, Staeger MA, Stewart AO, Stout DM, Zhu G-D (2000) Preparation of thienopyridines and thienopyrimidines as cell adhesion-inhibiting antiinflammatory compounds. Chem Abstr 134:353297 (WIPO 075145, Jun 28, 1999; (2001))
Zhang Y, Wang Z, Zhang X, Guo J, Hu J, Hua X, Chu W, An H, Qin Y, Wu H, Mu Y, Shi H, Geng J (2021) Preparation of the compound as NMTt inhibitor and their medical applications. Chem Abstr 174:310310 (WO 2021008512, Jan 21, 2021; (2021))
Dunn AD, Norrie R (1987) J Heterocycl Chem 24:85
Morrow BJ, Camerino MA, Walker SR, Stevenson GI, Stupple PA (2019) Substituted condensed thiophenes as modulators of STING protein and their preparation. Chem Abstr 172:25199 (WO 2019219820, Nov 21, 2019; (2019))
Lee J, Kirincich SJ, Smith MJ, Wilson DP, Follows BC, Wan Z-K, Joseph-Mccarthy DM, Erbe DV, Zhang Y-L, Xu W, Tam SY (2005) Preparation of bicyclic fused thiophene inhibitors of protein tyrosine phosphatase 1B for treating diabetes and related diseases. Chem Abstr 143:266909 (WO 2005081960, Sep 9, 2005; (2005))
Zhu GD, Gunawardana IW, Boyd SA, Melcher LM (2008) J Heterocycl Chem 45:91
Homberger KR, Berger DM, Chen X, Crew AP, Dong H, Kleinberg A, Li A-H, Ma L, Mulvihill MJ, Panicker B, Siu KW, Steinig AG, Tarrant JG, Wang J, Weng Q, Sangem R, Gupta RC (2011) Preparation of 7-aminofuropyridine derivatives as TAK1 inhibitors. Chem Abstr 155:328304 (WO 2011100502, Aug 18, 2011; (2011))
Allen JG, Bourbeau MP, Dominguez C, Fotsch CH, Han N, Hong F-T, Huang X, Lee MR, Liu Q, Reichelt A, Tadesse S, Wang X, Yao G, Yuan CC, Zeng Q (2009) Preparation of thiadiazole compounds as protein kinase B (PKB) modulators. Chem Abstr 150:144489 (WO 2009011871, Jan 22, 2009; (2009))
Che C, Li S, Yang B, Xin S, Yu Z, Shao T, Tao C, Lin S, Yang Z (2012) Beilstein J Org Chem 8:841
Huff CA, Cohen RD, Dykstra KD, Streckfuss E, DiRocco DA, Krska SW (2016) J Org Chem 81:6980
Cannavo A, Komici K, Bencivenga L, D’amico ML, Gambino G, Liccardo D, Ferrara N, Rengo G (2018) Expert Opin Ther Targets 22:75
Guccione M, Ettari R, Taliani S, Da Settimo F, Zappalà M, Grasso S (2016) J Med Chem 59:9277
Okawa T, Aramaki Y, Yamamoto M, Kobayashi T, Fukumoto S, Toyoda Y, Henta T, Hata A, Ikeda S, Kaneko M, Hoffman ID, Sang B-C, Zou H, Kawamoto T (2017) J Med Chem 60:6942
Leach AR, Hann MM, Burrows JN, Griffen EJ (2006) Mol Biosyst 2:429
Acknowledgements
We are grateful to the Analytical Division of the Servier Research Institute of Medicinal Chemistry for providing the analytical characterizations.
Author information
Authors and Affiliations
Corresponding authors
Additional information
This manuscript is dedicated with gratitude to the memory of the late Prof. Fritz Sauter, an unrelenting advocate of cross-border scientific communities.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Balo, T., Sapi, A., Kiss, A. et al. Synthesis of thieno[2,3-c]pyridine derived GRK2 inhibitors. Monatsh Chem 154, 1339–1357 (2023). https://doi.org/10.1007/s00706-021-02889-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00706-021-02889-2