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Future Medicinal Chemistry Volume 4, 2012 - Issue 11
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Review

Macrocycles In New Drug Discovery

Jamie MallinsonCancer Research UK Cancer Therapeutics Unit, Institute of Cancer Research, 15 Cotswold Road, Sutton, SurreySM2 5NG, UKView further author information
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Ian CollinsCancer Research UK Cancer Therapeutics Unit, Institute of Cancer Research, 15 Cotswold Road, Sutton, SurreySM2 5NG, UKCorrespondence[email protected]
View further author information
Pages 1409-1438 | Published online: 02 Aug 2012

References

  • Driggers EM , HaleSP, LeeJ, TerrettNK. The exploration of macrocycles for drug discovery – an underexploited structural class.Nat. Rev. Drug Discov.7(7), 608–624 (2008).
  • Oyelere AK . Macrocycles in medicinal chemistry and drug discovery.Curr. Top. Med. Chem.10(14), 1359–1360 (2010).
  • Marsault E , PetersonML. Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery.J. Med. Chem.54(7), 1961–2004 (2011).
  • Avolio S , SummaV. Advances in the development of macrocyclic inhibitors of hepatitis C virus NS3–4A protease.Curr. Top. Med. Chem.10(14), 1403–1422 (2010).
  • Brandt W , HauptVJ, WessjohannLA. Chemoinformatic analysis of biologically active macrocycles.Curr. Top. Med. Chem.10(14), 1361–1379 (2010).
  • Giamarellos-Bourboulis EJ . Macrocycle molecules for the management of systemic infections: the clarithromycin paradigm.Curr. Top. Med. Chem.10(14), 1470–1475 (2010).
  • Johnson VA , SinghEK, NazarovaLA, AlexanderLD, McalpineSR. Macrocyclic inhibitors of hsp90.Curr. Top. Med. Chem.10(14), 1380–1402 (2010).
  • Mwakwari SC , PatilV, GuerrantW, OyelereAK. Macrocyclic histone deacetylase inhibitors.Curr. Top. Med. Chem.10(14), 1423–1440 (2010).
  • Ying L , TangD. Recent advances in the medicinal chemistry of novel erythromycin-derivatized antibiotics.Curr. Top. Med. Chem.10(14), 1441–1469 (2010).
  • Smith B , MarchJ. March’s Advanced Organic Chemistry: Reactions, Mechanisms and Structure (5th Edition). Wiley, New York, NY, USA, 184–186 (2001).
  • Wessjohann LA , RuijterE, Garcia-RiveraD, BrandtW. What can a chemist learn from nature’s macrocycles? A brief, conceptual view.Mol. Divers.9(1), 171–186 (2005).
  • Kwitkowski VE , ProwellTM, IbrahimAet al. FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma. Oncologist 15(4), 428–435 (2010).
  • Raymond E , AlexandreJ, FaivreSet al. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J. Clin. Oncol. 22(12), 2336–2347 (2004).
  • Conlin A , FornierM, HudisC, KarS, KirkpatrickP. Ixabepilone.Nat. Rev. Drug Discov.6(12), 953–954 (2007).
  • Goodin S . Novel cytotoxic agents: epothilones.Am. J. Health Syst. Pharm.65(10, Suppl. 3), S10–S15 (2008).
  • Goodin S . Ixabepilone: a novel microtubule-stabilizing agent for the treatment of metastatic breast cancer.Am. J. Health Syst. Pharm.65(21), 2017–2026 (2008).
  • Mcdonald E , WorkmanP, JonesK. Inhibitors of the HSP90 molecular chaperone: attacking the master regulator in cancer.Curr. Top. Med. Chem.6(11), 1091–1107 (2006).
  • Hart S , GohKC, Novotny-DiermayrVet al. SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies. Leukemia 25(11), 1751–1759 (2011).
  • Komrojki RS , WadleighM, SeymourJFet al. Results of a Phase 2 study of pacritinib (SB1518), a novel oral JAK2 inhibitor, in patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis. Presented at: 53rd ASH Annual Meeting and Exposition. San Diego Convention Center, San Diego, CA, USA, 10–13 December 2011.
  • William AD , LeeACH, GohKCet al. Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), janus kinase 2 (JAK2), and Fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer. J. Med. Chem. 55(1), 169–196 (2012).
  • Mas-Moruno C , RechenmacherF, KesslerH. Cilengitide: the first anti-angiogenic small molecule drug candidate. design, synthesis and clinical evaluation.Anticancer Agents Med. Chem.10(10), 753–768 (2010).
  • Stupp R , Van Den BentMJ, ErridgeSCet al. Cilengitide in newly diagnosed glioblastoma with MGMT promoter methylation: Protocol of a multicenter, randomized, open-label, controlled phase III trial (CENTRIC). J. Clin. Oncol.28(15s), TPS152 (2010).
  • Hirai H , Takahashi-SuzikiI, ShimomuraTet al. Potent anti-tumor activity of a macrocycle-quinoxalinone class pan-Cdk inhibitor in vitro and in vivo. Invest. New Drugs 29(4), 534–543 (2011).
  • Lipinski CA , LombardoF, DominyBW, FeeneyPJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings.Adv. Drug Deliv. Rev.46(1–3), 3–26 (2001).
  • Collins I , WorkmanP. New approaches to molecular cancer therapeutics.Nat. Chem Biol.2(12), 689–700 (2006).
  • Lipinski CA . Compound properties and drug quality. In: In The Practice of Medicinal Chemistry (Second Edition). Wermuth C (Ed.). Academic Press, London, UK, 341 (2003).
  • Vieth M , SiegelMG, HiggsREet al. Characteristic physical properties and structural fragments of marketed oral drugs. J. Med. Chem. 47(1), 224–232 (2004).
  • Veber DF , JohnsonSR, Cheng H-Y, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem.45(12), 2615–2623 (2002).
  • Lu JJ , CriminK, GoodwinJTet al. Influence of molecular flexibility and polar surface area metrics on oral bioavailability in the rat. J. Med. Chem. 47(24), 6104–6107 (2004).
  • Harvey AL . Natural products in drug discovery.Drug Discov. Today13(19–20), 894–901 (2008).
  • Mann A . Conformational restriction and/or steric hindrance in medicinal chemistry. In: The Practice Of Medicinal Chemistry, Wermuth CG (Ed.). Academic Press, London, UK (2008).
  • Reynolds CH , HollowayMK. Thermodynamics of ligand binding and efficiency.ACS Med. Chem. Lett.2(6), 433–437 (2011).
  • Bissantz C , KuhnB, StahlM. A medicinal chemist’s guide to molecular interactions.J. Med. Chem.53(14), 5061–5084 (2010).
  • Sarkar A , KelloggGE. Hydrophobicity – shake flasks, protein folding and drug discovery.Curr. Top Med. Chem.10(1), 67–83 (2010).
  • Williams DH , CalderoneCT, O‘BrienDP, ZerellaR. Changes in motion vs. bonding in positively vs. negatively cooperative interactions.Chem. Comm. (12), 1266–1267 (2002).
  • DeLorbe JE , ClementsJH, WhiddonBB, MartinSF. Thermodynamic and structural effects of macrocyclic constraints in protein–ligand interactions.ACS Med. Chem. Lett.1(8), 448–452 (2010).
  • Tao Z -F, Wang L, Stewart KD et al. Structure-based design, synthesis, and biological evaluation of potent and selective macrocyclic checkpoint kinase 1 inhibitors. J. Med. Chem.50(7), 1514–1527 (2007).
  • Proisy N , SharpSY, BoxallKet al. Inhibition of Hsp90 with synthetic macrolactones: synthesis and structural and biological evaluation of ring and conformational analogs of radicicol. Chem. Biol. 13(11), 1203–1215 (2006).
  • Lücking U , SiemeisterG, SchäferMet al. Macrocyclic aminopyrimidines as multitarget CDK and VEGF-R inhibitors with potent antiproliferative activities. ChemMedChem 2(1), 63–77 (2007).
  • Nie Z , PerrettaC, EricksonPet al. Structure-based design and synthesis of novel macrocyclic pyrazolo[1,5-a][1,3,5]triazine compounds as potent inhibitors of protein kinase CK2 and their anticancer activities. Bioorg. Med. Chem. Lett. 18(2), 619–623 (2008).
  • Ishikawa M , HashimotoY. Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry.J. Med. Chem.54(6), 1539–1554 (2011).
  • Lovering F , BikkerJ, HumbletC. Escape from flatland: increasing saturation as an approach to improving clinical success.J. Med. Chem.52(21), 6752–6756 (2009).
  • Huang Y , StrobelED, HoCYet al. Macrocyclic BACE inhibitors: optimization of a micromolar hit to nanomolar leads. Bioorg. Med. Chem. Lett. 20(10), 3158–3160 (2010).
  • Baxter EW , ConwayKA, KennisLet al. 2-amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (β-site APP cleaving enzyme): use of structure based design to convert a micromolar hit into a nanomolar lead. J. Med. Chem. 50(18), 4261–4264 (2007).
  • Stachel SJ , CoburnCA, SankaranarayananSet al. Macrocyclic inhibitors of β-secretase: functional activity in an animal model. J. Med. Chem. 49(21), 6147–6150 (2006).
  • Hopkins AL , GroomCR, AlexA. Ligand efficiency: a useful metric for lead selection.Drug Discov. Today9(10), 430–431 (2004).
  • Zhang H -C, Boñaga LVR, Ye H, Derian CK, Damiano BP, Maryanoff BE. Novel bis(indolyl)maleimide pyridinophanes that are potent, selective inhibitors of glycogen synthase kinase-3. Bioorg. Med. Chem. Lett.17(10), 2863–2868 (2007).
  • Bartlett S , BeddardGS, JacksonRMet al. Comparison of the ATP binding sites of protein kinases using conformationally diverse bisindolylmaleimides. J. Am. Chem. Soc. 127(33), 11699–11708 (2005).
  • Dakas P -Y, Barluenga S, Totzke F, Zirrgiebel U, Winssinger N. Modular synthesis of radicicol a and related resorcylic acid lactones, potent kinase inhibitors. Angew. Chem. Int. Ed. Engl.46(36), 6899–6902 (2007).
  • Jogireddy R , Dakas P-Y, Valot G, Barluenga S, Winssinger N. Synthesis of a resorcylic acid lactone (RAL) library using fluorous-mixture synthesis and profile of its selectivity against a panel of kinases. Chem. Eur. J.15(43), 11498–11506 (2009).
  • Moulin E , BarluengaS, WinssingerN. Concise synthesis of pochonin A, an HSP90 inhibitor.Org. Lett.7(25), 5637–5639 (2005).
  • Moulin E , BarluengaS, TotzkeF, WinssingerN. Diversity-oriented synthesis of pochonins and biological evaluation against a panel of kinases.Chem. Eur. J.12(34), 8819–8834 (2006).
  • Sund C , BeldaO, WikteliusDet al. Design and synthesis of potent macrocyclic renin inhibitors. Bioorg. Med. Chem. Lett. 21(1), 358–362 (2011).
  • Linde Y , OvadiaO, SafraiEet al. Structure–activity relationship and metabolic stability studies of backbone cyclization and N-methylation of melanocortin peptides. Peptide Sci. 90(5), 671–682 (2008).
  • Horswill AR , BenkovicSJ. Cyclic peptides, a chemical genetics tool for biologists.Cell Cycle4(4), 552–555 (2005).
  • Mesaros EF , BurkeJP, ParrishJDet al. Novel 2,3,4,5-tetrahydro-benzo[d]azepine derivatives of 2,4-diaminopyrimidine, selective and orally bioavailable ALK inhibitors with antitumor efficacy in ALCL mouse models. Bioorg. Med. Chem. Lett. 21(1), 463–466 (2011).
  • Breslin HJ , LaneBM, OttGRet al. Design, synthesis, and anaplastic lymphoma kinase (ALK) inhibitory activity for a novel series of 2,4,8,22-tetraazatetracyclo[14.3.1.13,7.19,13]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles. J. Med. Chem. 55(1), 449–464 (2011).
  • Zapf CW , BloomJD, LiZet al. Discovery of a stable macrocyclic o-aminobenzamide Hsp90 inhibitor which significantly decreases tumor volume in a mouse xenograft model. Bioorg. Med. Chem. Lett. 21(15), 4602–4607 (2011).
  • Zapf CW , BloomJD, McbeanJLet al. Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with heterocyclic tether that shows extended biomarker activity and in vivo efficacy in a mouse xenograft model. Bioorg. Med. Chem. Lett. 21(12), 3627–3631 (2011).
  • Zapf CW , BloomJD, McbeanJLet al. Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity. Bioorg. Med. Chem. Lett. 21(8), 2278–2282 (2011).
  • Zapf CW , BloomJD, McbeanJLet al. Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity. Bioorg. Med. Chem. Lett. 21(11), 3411–3416 (2011).
  • Huang KH , VealJM, FaddenRPet al. Discovery of novel 2-aminobenzamide inhibitors of heat shock protein 90 as potent, selective and orally active antitumor agents. J. Med. Chem. 52(14), 4288–4305 (2009).
  • Cho YS , WhiteheadL, LiJet al. Conformational refinement of hydroxamate-based histone deacetylase inhibitors and exploration of 3-piperidin-3-ylindole analogues of dacinostat (LAQ824). J. Med. Chem. 53(7), 2952–2963 (2010).
  • Collins I , RowleyM, DaveyWBet al. 3-(1-piperazinyl)-4,5-dihydro-1H-benzo[g]indazoles: high affinity ligands for the human dopamine D4 receptor with improved selectivity over ion channels. Bioorg. Med. Chem. 6(6), 743–753 (1998).
  • Kawanishi N , SugimotoT, ShibataJet al. Structure-based drug design of a highly potent CDK1,2,4,6 inhibitor with novel macrocyclic quinoxalin-2-one structure. Bioorg. Med. Chem. Lett. 16(19), 5122–5126 (2006).
  • William AD , LeeACH, BlanchardSPet al. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent janus kinase 2/Fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J. Med. Chem. 54(13), 4638–4658 (2011).
  • Rezai T , BockJE, ZhouMV, KalyanaramanC, LokeyRS, JacobsonMP. Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: successful in silico prediction of the relative permeabilities of cyclic peptides. J. Am. Chem. Soc.128(43), 14073–14080 (2006).
  • Rezai T , YuB, MillhauserGL, JacobsonMP, LokeyRS. Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers.J. Am. Chem. Soc.128(8), 2510–2511 (2006).
  • Augustijns PF , BrownSC, WillardDHet al. Hydration changes implicated in the remarkable temperature-dependent membrane permeation of cyclosporin A. Biochemistry 39(25), 7621–7630 (2000).
  • Kessler H , KöckM, WeinT, GehrkeM. Reinvestigation of the conformation of cyclosporin A in chloroform.Helv. Chim. Acta73(7), 1818–1832 (1990).
  • Ko SY , DalvitC. Conformation of cyclosporin A in polar solvents.Int. J. Pept. Protein Res.40(5), 380–382 (1992).
  • Terrett NK . Methods for the synthesis of macrocycle libraries for drug discovery.Drug Discov. Today: Technologies7(2), e97–e104 (2010).
  • Bogdan AR , DaviesNL, JamesK. Comparison of diffusion coefficients for matched pairs of macrocyclic and linear molecules over a drug-like molecular weight range.Org. Biomol. Chem.9(22), 7727–7733 (2011).
  • Day JEH , SharpSY, RowlandsMGet al. Targeting the Hsp90 molecular chaperone with novel macrolactams. synthesis, structural, binding, and cellular studies. ACS Chem. Biol. 6(12), 1339–1347 (2011).
  • Hunt JT . Discovery of ixabepilone.Mol. Cancer Ther.8(2), 275–281 (2009).
  • Wessjohann LA , RuijterE. Strategies for total and diversity-oriented synthesis of natural product(-like) macrocycles. In: Natural Product Synthesis I. Mulzer J (Ed.). Springer, Heidelberg, Berlin, Germany, 137–184 (2005).
  • Lee CW , GrubbsRH. Formation of macrocycles via ring-closing olefin metathesis.J. Org. Chem.66(21), 7155–7158 (2001).
  • Tao Z -F, Sowin TJ, Lin N-H. Synthesis of macrocyclic urea kinase inhibitors. Synlett18, 2855–2858 (2007).
  • Dandapani S , MarcaurelleLA. Grand challenge commentary: accessing new chemical space for ‘undruggable’ targets.Nat. Chem. Biol.6(12), 861–863 (2010).
  • Yu M , WangC, KyleAFet al. Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis. Nature 479(7371), 88–93 (2011).
  • Kim MJ , LeeSH, ParkSOet al. Novel macrocyclic C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents. Bioorg. Med. Chem. 19(18), 5468–5479 (2011).
  • Winssinger N , BarluengaS. Chemistry and biology of resorcylic acid lactones.Chem. Commun. (1), 22–36 (2007).
  • Dakas P -Y, Jogireddy R, Valot G, Barluenga S, Winssinger N. Divergent syntheses of resorcylic acid lactones: L-783277, LL-Z1640–2, and hypothemycin. Chem. Eur. J.15(43), 11490–11497 (2009).
  • Balraju V , IqbalJ. Synthesis of cyclic peptides constrained with biarylamine linkers using Buchwald–Hartwig C-N coupling.J. Org. Chem.71(23), 8954–8956 (2006).
  • Bogdan AR , JamesK. Synthesis of 5-iodo-1,2,3-triazole-containing macrocycles using copper flow reactor technology.Organic Letters13(15), 4060–4063 (2011).
  • Chouhan G , JamesK. CuAAC macrocyclization: high intramolecular selectivity through the use of copper–tris(triazole) ligand complexes. Org. Lett.13(10), 2754–2757 (2011).
  • Malet Sanz L , SusanneF. Continuous flow synthesis. a pharma perspective.J. Med. Chem.55(9), 4062–4098 (2012).
  • White CJ , YudinAK. Contemporary strategies for peptide macrocyclization.Nat. Chem.3(7), 509–524 (2011).
  • Tse BN , SnyderTM, ShenY, LiuDR. Translation of DNA into a library of 13,000 synthetic small-molecule macrocycles suitable for in vitro selection. J. Am. Chem. Soc.130(46), 15611–15626 (2008).
  • Hoveyda HR , MarsaultE, GagnonRet al. Optimization of the potency and pharmacokinetic properties of a macrocyclic ghrelin receptor agonist (part I): development of ulimorelin (TZP-101) from hit to clinic. J. Med. Chem. 54(24), 8305–8320 (2011).
  • Rudd MT , MccauleyJA, ButcherJWet al. Discovery of MK-1220: a macrocyclic inhibitor of hepatitis C virus NS3/4A Protease with improved preclinical plasma exposure. ACS Med. Chem. Lett. 2(3), 207–212 (2011).
  • Hann MM . Molecular obesity, potency and other addictions in drug discovery.MedChemComm2(5), 349–355 (2011).
  • Faivre S , KroemerG, RaymondE. Current development of mTOR inhibitors as anticancer agents.Nat. Rev. Drug Discov.5(8), 671–688 (2006).
  • Choi J , ChenJ, SchreiberSL, JonC. Structure of the FKBP12–rapamycin complex interacting with the binding domain of human FRAP.Science273, 239–242 (1996).
  • Heinz DW , Schubert W-D, Höfle G. Much anticipated – the bioactive conformation of epothilone and its binding to tubulin. Angew. Chem. Int. Ed. Engl.44(9), 1298–1301 (2005).
  • Nettles JH , LiH, CornettB, KrahnJM, SnyderJP, DowningKH. The binding mode of epothilone A on α,β-tubulin by electron crystallography.Science305(5685), 866–869 (2004).
  • Hung AW , RamekA, WangYet al. Route to three-dimensional fragments using diversity-oriented synthesis. Proc. Natl Acad. Sci. USA 108(17), 6799–6804 (2011).
  • Ritchie TJ , MacdonaldSJF. The impact of aromatic ring count on compound developability – are too many aromatic rings a liability in drug design?Drug Discov. Today14(21–22), 1011–1020 (2009).
  • Banerji U , O‘DonnellA, ScurrMet al. Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J. Clin. Oncol. 23(18), 4152–4161 (2005).

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