Macrocycles in new drug discovery.

The use of drug-like macrocycles is emerging as an exciting area of medicinal chemistry, with several recent examples highlighting the favorable changes in biological and physicochemical properties that macrocyclization can afford. Natural product macrocycles and their synthetic derivatives have long been clinically useful and attention is now being focused on the wider use of macrocyclic scaffolds in medicinal chemistry in the search for new drugs for increasingly challenging targets. With the increasing awareness of concepts of drug-likeness and the dangers of 'molecular obesity', functionalized macrocyclic scaffolds could provide a way to generate ligand-efficient molecules with enhanced properties. In this review we will separately discuss the effects of macrocyclization upon potency, selectivity and physicochemical properties, concentrating on recent case histories in oncology drug discovery. Additionally, we will highlight selected advances in the synthesis of macrocycles and provide an outlook on the future use of macrocyclic scaffolds in medicinal chemistry.

[1]  Matthew P Jacobson,et al.  Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers. , 2006, Journal of the American Chemical Society.

[2]  Martin Brassard,et 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. , 2011, Journal of medicinal chemistry.

[3]  Anders Poulsen,et 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 lympho , 2011, Journal of medicinal chemistry.

[4]  F. Totzke,et al.  Diversity-oriented synthesis of pochonins and biological evaluation against a panel of kinases. , 2006, Chemistry.

[5]  A. Mann Conformational Restriction and/or Steric Hindrance in Medicinal Chemistry , 2008 .

[6]  R. Stupp,et al.  Cilengitide in newly diagnosed glioblastoma with MGMT promoter methylation: Protocol of a multicenter, randomized, open-label, controlled phase III trial (CENTRIC). , 2010 .

[7]  S. Barluenga,et al.  Synthesis of a resorcylic acid lactone (RAL) library using fluorous-mixture synthesis and profile of its selectivity against a panel of kinases. , 2009, Chemistry.

[8]  H. Hirai,et al.  Structure-based drug design of a highly potent CDK1,2,4,6 inhibitor with novel macrocyclic quinoxalin-2-one structure. , 2006, Bioorganic & medicinal chemistry letters.

[9]  Ian Collins,et al.  New approaches to molecular cancer therapeutics , 2006, Nature chemical biology.

[10]  David R. Liu,et al.  Translation of DNA into a library of 13,000 synthetic small-molecule macrocycles suitable for in vitro selection. , 2008, Journal of the American Chemical Society.

[11]  Alan L Harvey,et al.  Natural products in drug discovery. , 2008, Drug discovery today.

[12]  P. Atadja,et al.  Conformational refinement of hydroxamate-based histone deacetylase inhibitors and exploration of 3-piperidin-3-ylindole analogues of dacinostat (LAQ824). , 2010, Journal of medicinal chemistry.

[13]  Matthew P Jacobson,et al.  Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: successful in silico prediction of the relative permeabilities of cyclic peptides. , 2006, Journal of the American Chemical Society.

[14]  S. Barluenga,et al.  Concise synthesis of pochonin A, an HSP90 inhibitor. , 2005, Organic letters.

[15]  M. Vandermeeren,et al.  Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads. , 2010, Bioorganic & medicinal chemistry letters.

[16]  J. H. Clements,et al.  Thermodynamic and Structural Effects of Macrocyclization as a Constraining Method in Protein-Ligand Interactions. , 2010, ACS medicinal chemistry letters.

[17]  T. Ritchie,et al.  The impact of aromatic ring count on compound developability--are too many aromatic rings a liability in drug design? , 2009, Drug discovery today.

[18]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.

[19]  Jun-ichi Yoshida,et al.  Continuous flow synthesis. , 2013, Drug discovery today. Technologies.

[20]  S. Benkovic,et al.  Cyclic Peptides, A Chemical Genetics Tool for Biologists , 2005, Cell cycle.

[21]  S. Goodin Ixabepilone: a novel microtubule-stabilizing agent for the treatment of metastatic breast cancer. , 2008, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[22]  Horst Kessler,et al.  Reinvestigation of the Conformation of Cyclosporin A in Chloroform , 1990 .

[23]  Alessia Pica,et al.  Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  L. To,et 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 , 2011 .

[25]  S. Goodin Novel cytotoxic agents: epothilones. , 2008, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[26]  Glen E Kellogg,et al.  Hydrophobicity--shake flasks, protein folding and drug discovery. , 2010, Current topics in medicinal chemistry.

[27]  J. Levin,et al.  Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity. , 2011, Bioorganic & medicinal chemistry letters.

[28]  Chang Park,et al.  Structure-based design, synthesis, and biological evaluation of potent and selective macrocyclic checkpoint kinase 1 inhibitors. , 2007, Journal of medicinal chemistry.

[29]  A. Bogdan,et al.  Comparison of diffusion coefficients for matched pairs of macrocyclic and linear molecules over a drug-like molecular weight range. , 2011, Organic & biomolecular chemistry.

[30]  Victoria A Johnson,et al.  Macrocyclic inhibitors of hsp90. , 2010, Current topics in medicinal chemistry.

[31]  A. Ghose,et 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. , 2012, Journal of medicinal chemistry.

[32]  H. Briem,et al.  Macrocyclic Aminopyrimidines as Multitarget CDK and VEGF‐R Inhibitors with Potent Antiproliferative Activities , 2007, ChemMedChem.

[33]  Laura G. Dubois,et al.  Discovery of novel 2-aminobenzamide inhibitors of heat shock protein 90 as potent, selective and orally active antitumor agents. , 2009, Journal of medicinal chemistry.

[34]  E. Raymond,et al.  Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  Paul Workman,et al.  Inhibitors of the HSP90 molecular chaperone: attacking the master regulator in cancer. , 2006, Current topics in medicinal chemistry.

[36]  Synthesis of cyclic peptides constrained with biarylamine linkers using Buchwald-Hartwig C-N coupling. , 2006, The Journal of organic chemistry.

[37]  Junya Qu,et al.  2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-site APP cleaving enzyme): Use of structure based design to convert a micromolar hit into a nanomolar lead. , 2007, Journal of medicinal chemistry.

[38]  P. Clemons,et al.  Route to three-dimensional fragments using diversity-oriented synthesis , 2011, Proceedings of the National Academy of Sciences.

[39]  Stephen P. Hale,et al.  The exploration of macrocycles for drug discovery — an underexploited structural class , 2008, Nature Reviews Drug Discovery.

[40]  Dudley H. Williams,et al.  Changes in motion vs. bonding in positively vs. negatively cooperative interactions. , 2002, Chemical communications.

[41]  Christopher J. White,et al.  Contemporary strategies for peptide macrocyclization. , 2011, Nature chemistry.

[42]  A. Hopkins,et al.  Ligand efficiency: a useful metric for lead selection. , 2004, Drug discovery today.

[43]  J. Levin,et al.  Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity. , 2011, Bioorganic & medicinal chemistry letters.

[44]  Paul Workman,et al.  Inhibition of Hsp90 with synthetic macrolactones: synthesis and structural and biological evaluation of ring and conformational analogs of radicicol. , 2006, Chemistry & biology.

[45]  C. Gilon,et al.  Structure-activity relationship and metabolic stability studies of backbone cyclization and N-methylation of melanocortin peptides. , 2008, Biopolymers.

[46]  S. Barluenga,et al.  Divergent syntheses of resorcylic acid lactones: L-783277, LL-Z1640-2, and hypothemycin. , 2009, Chemistry.

[47]  M. Hann Molecular obesity, potency and other addictions in drug discovery , 2011 .

[48]  Min Ju Kim,et al.  Novel macrocyclic C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents. , 2011, Bioorganic & medicinal chemistry.

[49]  Andrew G. Leach,et al.  Comparison of the ATP binding sites of protein kinases using conformationally diverse bisindolylmaleimides. , 2005, Journal of the American Chemical Society.

[50]  J. Hunt Discovery of Ixabepilone , 2009, Molecular Cancer Therapeutics.

[51]  G. Kroemer,et al.  Current development of mTOR inhibitors as anticancer agents , 2006, Nature Reviews Drug Discovery.

[52]  S. Brown,et al.  Hydration changes implicated in the remarkable temperature-dependent membrane permeation of cyclosporin A. , 2000, Biochemistry.

[53]  H. Hirai,et al.  Potent anti-tumor activity of a macrocycle-quinoxalinone class pan-Cdk inhibitor in vitro and in vivo , 2011, Investigational New Drugs.

[54]  C. Humblet,et al.  Escape from flatland: increasing saturation as an approach to improving clinical success. , 2009, Journal of medicinal chemistry.

[55]  N. Terrett,et al.  Methods for the synthesis of macrocycle libraries for drug discovery. , 2010, Drug discovery today. Technologies.

[56]  Ludger A. Wessjohann,et al.  What can a chemist learn from nature’s macrocycles? – A brief, conceptual view , 2005, Molecular Diversity.

[57]  L. Pearl,et al.  Targeting the Hsp90 molecular chaperone with novel macrolactams. Synthesis, structural, binding, and cellular studies. , 2011, ACS chemical biology.

[58]  H. Ye,et al.  Novel bis(indolyl)maleimide pyridinophanes that are potent, selective inhibitors of glycogen synthase kinase-3. , 2007, Bioorganic & medicinal chemistry letters.

[59]  Ben Cornett,et al.  The Binding Mode of Epothilone A on α,ß-Tubulin by Electron Crystallography , 2004, Science.

[60]  Vincenzo Summa,et al.  Advances in the development of macrocyclic inhibitors of hepatitis C virus NS3-4A protease. , 2010, Current topics in medicinal chemistry.

[61]  Jerry March,et al.  March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure , 2001 .

[62]  R. Pazdur,et al.  FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma. , 2010, The oncologist.

[63]  C. Perretta,et 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. , 2008, Bioorganic & medicinal chemistry letters.

[64]  S. Lakhani,et al.  Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[65]  Wolfgang Brandt,et al.  Chemoinformatic analysis of biologically active macrocycles. , 2010, Current topics in medicinal chemistry.

[66]  Sandra C. Mwakwari,et al.  Macrocyclic histone deacetylase inhibitors. , 2010, Current topics in medicinal chemistry.

[67]  Andrew V. Anzalone,et 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. , 2011, Bioorganic & medicinal chemistry letters.

[68]  Sivaraman Dandapani,et al.  Grand challenge commentary: Accessing new chemical space for 'undruggable' targets. , 2010, Nature chemical biology.

[69]  Minoru Ishikawa,et al.  Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry. , 2011, Journal of medicinal chemistry.

[70]  Li Xing,et al.  Influence of molecular flexibility and polar surface area metrics on oral bioavailability in the rat. , 2004, Journal of medicinal chemistry.

[71]  D. Heinz,et al.  Much anticipated--the bioactive conformation of epothilone and its binding to tubulin. , 2005, Angewandte Chemie.

[72]  Stuart L. Schreiber,et al.  Structure of the FKBP12-Rapamycin Complex Interacting with Binding Domain of Human FRAP , 1996, Science.

[73]  J. Levin,et 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. , 2011, Bioorganic & medicinal chemistry letters.

[74]  A. Bogdan,et al.  Synthesis of 5-iodo-1,2,3-triazole-containing macrocycles using copper flow reactor technology. , 2011, Organic letters.

[75]  M. Holloway,et al.  Thermodynamics of ligand binding and efficiency. , 2011, ACS medicinal chemistry letters.

[76]  Ian A. Watson,et al.  Characteristic physical properties and structural fragments of marketed oral drugs. , 2004, Journal of medicinal chemistry.

[77]  J. Wood,et al.  Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-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- , 2012, Journal of medicinal chemistry.

[78]  A. Oyelere,et al.  Editorial [Hot topic: Macrocycles in Medicinal Chemistry and Drug Discovery (Guest Editors: Adegboyega K. Oyelere)] , 2010 .

[79]  Horst Kessler,et al.  Cilengitide: The First Anti-Angiogenic Small Molecule Drug Candidate. Design, Synthesis and Clinical Evaluation , 2010, Anti-cancer agents in medicinal chemistry.

[80]  R. Schrock,et al.  Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis , 2011, Nature.

[81]  J. Levin,et al.  Discovery of a stable macrocyclic o-aminobenzamide Hsp90 inhibitor which significantly decreases tumor volume in a mouse xenograft model. , 2011, Bioorganic & medicinal chemistry letters.

[82]  Jerry March,et al.  Advanced Organic Chemistry: Reactions, Mechanisms, and Structure , 1977 .

[83]  Stephen R. Johnson,et al.  Molecular properties that influence the oral bioavailability of drug candidates. , 2002, Journal of medicinal chemistry.

[84]  É. Marsault,et al.  Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery. , 2011, Journal of medicinal chemistry.

[85]  R. Grubbs,et al.  Formation of macrocycles via ring-closing olefin metathesis. , 2001, The Journal of organic chemistry.

[86]  M. Katharine Holloway,et al.  Macrocyclic Inhibitors of β-Secretase: Functional Activity in an Animal Model. , 2006 .

[87]  Z. Tao,et al.  Synthesis of Macrocyclic Urea Kinase Inhibitors , 2007 .

[88]  S. Barluenga,et al.  Chemistry and biology of resorcylic acid lactones. , 2007, Chemical communications.

[89]  C. Dalvit,et al.  Conformation of cyclosporin A in polar solvents. , 2009, International journal of peptide and protein research.

[90]  P. Leeson,et 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. , 1998, Bioorganic & medicinal chemistry.

[91]  K. James,et al.  CuAAC macrocyclization: high intramolecular selectivity through the use of copper-tris(triazole) ligand complexes. , 2011, Organic letters.

[92]  N. Borkakoti,et al.  Design and synthesis of potent macrocyclic renin inhibitors. , 2011, Bioorganic & medicinal chemistry letters.

[93]  M. Rudd,et al.  Discovery of MK-1220: A Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease with Improved Preclinical Plasma Exposure. , 2011, ACS medicinal chemistry letters.

[94]  Flavien Susanne,et al.  Continuous flow synthesis. A pharma perspective. , 2012, Journal of medicinal chemistry.

[95]  F. Totzke,et al.  Modular synthesis of radicicol A and related resorcylic acid lactones, potent kinase inhibitors. , 2007, Angewandte Chemie.

[96]  A. Poulsen,et al.  SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies , 2011, Leukemia.

[97]  C. Lipinski Compound Properties and Drug Quality , 2008 .