The Necessary Nitrogen Atom: A Versatile High-Impact Design Element for Multiparameter Optimization.

There is a continued desire in biomedical research to reduce the number and duration of design cycles required to optimize lead compounds into high-quality chemical probes or safe and efficacious drug candidates. The insightful application of impactful molecular design elements is one approach toward achieving this goal. The replacement of a CH group with a N atom in aromatic and heteroaromatic ring systems can have many important effects on molecular and physicochemical properties and intra- and intermolecular interactions that can translate to improved pharmacological profiles. In this Perspective, the "necessary nitrogen atom" is shown to be a versatile high-impact design element for multiparameter optimization, wherein ≥10-, 100-, or 1000-fold improvement in a variety of key pharmacological parameters can be realized.

[1]  J. Bajorath,et al.  Chemical Substitutions That Introduce Activity Cliffs Across Different Compound Classes and Biological Targets , 2010, J. Chem. Inf. Model..

[2]  Guomin Yao,et al.  N-substituted azaindoles as potent inhibitors of Cdc7 kinase. , 2013, Bioorganic & medicinal chemistry letters.

[3]  Yaxiong Sun,et al.  De novo prediction of p-glycoprotein-mediated efflux liability for druglike compounds. , 2013, ACS medicinal chemistry letters.

[4]  P. Portoghese,et al.  N-naphthoyl-β-naltrexamine (NNTA), a highly selective and potent activator of μ/κ-opioid heteromers , 2011, Proceedings of the National Academy of Sciences.

[5]  Y. Pommier,et al.  7-azaindenoisoquinolines as topoisomerase I inhibitors and potential anticancer agents. , 2011, Journal of medicinal chemistry.

[6]  M. A. Walker,et al.  Improving Solubility via Structural Modification , 2013 .

[7]  C. Fotsch,et al.  Mitigating heterocycle metabolism in drug discovery. , 2012, Journal of medicinal chemistry.

[8]  S. Muresan,et al.  Chemical predictive modelling to improve compound quality , 2013, Nature Reviews Drug Discovery.

[9]  H. Monenschein,et al.  Optimization of potency and pharmacokinetic properties of tetrahydroisoquinoline transient receptor potential melastatin 8 (TRPM8) antagonists. , 2014, Journal of medicinal chemistry.

[10]  S. Hitchcock,et al.  Structural modifications that alter the P-glycoprotein efflux properties of compounds. , 2012, Journal of medicinal chemistry.

[11]  W. L. Jorgensen,et al.  Energetics of displacing water molecules from protein binding sites: consequences for ligand optimization. , 2009, Journal of the American Chemical Society.

[12]  D A Dougherty,et al.  Cation-pi interactions in aromatics of biological and medicinal interest: electrostatic potential surfaces as a useful qualitative guide. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Shobha N. Bhattachar,et al.  Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor. , 2011, ACS medicinal chemistry letters.

[14]  Shuichi Sakamoto,et al.  Atropisomeric 4-phenyl-4H-1,2,4-triazoles as selective glycine transporter 1 inhibitors. , 2013, Journal of medicinal chemistry.

[15]  Aza follow-ups to BI 207524, a thumb pocket 1 HCV NS5B polymerase inhibitor. Part 1: Mitigating the genotoxic liability of an aniline metabolite. , 2015, Bioorganic & medicinal chemistry letters.

[16]  N. Walker,et al.  Optimization of novel di-substituted cyclohexylbenzamide derivatives as potent 11 beta-HSD1 inhibitors. , 2009, Bioorganic & medicinal chemistry letters.

[17]  B. Beno,et al.  A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design. , 2015, Journal of medicinal chemistry.

[18]  Elizabeth A. Amin,et al.  Tactical Approaches to Interconverting GPCR Agonists and Antagonists. , 2016, Journal of medicinal chemistry.

[19]  D. Fairlie,et al.  Potent heterocyclic ligands for human complement c3a receptor. , 2014, Journal of medicinal chemistry.

[20]  Shi Hua Ang,et al.  Discovery and Optimization of a Porcupine Inhibitor. , 2015, Journal of medicinal chemistry.

[21]  Christian Laurence,et al.  The pK(BHX) database: toward a better understanding of hydrogen-bond basicity for medicinal chemists. , 2009, Journal of medicinal chemistry.

[22]  Jürgen Bajorath,et al.  Matched molecular pairs derived by retrosynthetic fragmentation , 2014 .

[23]  Emanuele Perola,et al.  An analysis of the binding efficiencies of drugs and their leads in successful drug discovery programs. , 2010, Journal of medicinal chemistry.

[24]  C. A. Plank,et al.  Solubility of Benzene in Water. , 1958 .

[25]  Weilin Wu,et al.  Bis-aryl urea derivatives as potent and selective LIM kinase (Limk) inhibitors. , 2015, Journal of medicinal chemistry.

[26]  C. Sherrill,et al.  Effects of heteroatoms on aromatic pi-pi interactions: benzene-pyridine and pyridine dimer. , 2009, The journal of physical chemistry. A.

[27]  N. Carruthers,et al.  Synthesis, SAR, and Pharmacological Characterization of Brain Penetrant P2X7 Receptor Antagonists. , 2015, ACS medicinal chemistry letters.

[28]  T. Tomizaki,et al.  X-ray structure of the mouse serotonin 5-HT3 receptor , 2014, Nature.

[29]  P. Savy,et al.  Discovery of novel PI3-kinase δ specific inhibitors for the treatment of rheumatoid arthritis: taming CYP3A4 time-dependent inhibition. , 2012, Journal of medicinal chemistry.

[30]  Robert J. Young,et al.  Physical Properties in Drug Design , 2014 .

[31]  D. Holt,et al.  Identification of Purines and 7-Deazapurines as Potent and Selective Type I Inhibitors of Troponin I-Interacting Kinase (TNNI3K). , 2015, Journal of medicinal chemistry.

[32]  E. Parmee,et al.  The Impact of Chemical Probes in Drug Discovery: A Pharmaceutical Industry Perspective. , 2016, Cell chemical biology.

[33]  P. Selzer,et al.  Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. , 2000, Journal of medicinal chemistry.

[34]  D. Durden,et al.  Synthesis and cancer stem cell-based activity of substituted 5-morpholino-7H-thieno[3,2-b]pyran-7-ones designed as next generation PI3K inhibitors. , 2013, Journal of medicinal chemistry.

[35]  M. P. Dillon,et al.  Structure-Based Drug Design of Novel, Potent, and Selective Azabenzimidazoles (ABI) as ATR Inhibitors. , 2015, ACS medicinal chemistry letters.

[36]  Gregory W. Kauffman,et al.  A multi-endpoint matched molecular pair (MMP) analysis of 6-membered heterocycles. , 2017, Bioorganic & medicinal chemistry.

[37]  Yeon-Hee Lim,et al.  Use of molecular modeling aided design to dial out hERG liability in adenosine A(2A) receptor antagonists. , 2015, Bioorganic & medicinal chemistry letters.

[38]  Matthew D Segall,et al.  Multi-parameter optimization: identifying high quality compounds with a balance of properties. , 2012, Current pharmaceutical design.

[39]  Alexander Chuprina,et al.  Drug- and Lead-likeness, Target Class, and Molecular Diversity Analysis of 7.9 Million Commercially Available Organic Compounds Provided by 29 Suppliers , 2010, J. Chem. Inf. Model..

[40]  N. Chen,et al.  Novel vanilloid receptor-1 antagonists: 2. Structure-activity relationships of 4-oxopyrimidines leading to the selection of a clinical candidate. , 2007, Journal of medicinal chemistry.

[41]  Igor M. Prokopczyk,et al.  Hydrogen Bond Basicity Prediction for Medicinal Chemistry Design. , 2016, Journal of medicinal chemistry.

[42]  Mark T. Kershaw,et al.  Discovery of novel 6,6-heterocycles as transient receptor potential vanilloid (TRPV1) antagonists. , 2010, Journal of medicinal chemistry.

[43]  A. Kalgutkar,et al.  The Role of Biotransformation Studies in Reducing Drug Attrition , 2013 .

[44]  R. Bosotti,et al.  Cdc7 kinase inhibitors: pyrrolopyridinones as potential antitumor agents. 1. Synthesis and structure-activity relationships. , 2008, Journal of medicinal chemistry.

[45]  J. T. Njardarson,et al.  Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. , 2014, Journal of medicinal chemistry.

[46]  Robin Taylor,et al.  Hydrogen bonding properties of oxygen and nitrogen acceptors in aromatic heterocycles , 1997 .

[47]  Stephen D. Pickett,et al.  The developability of heteroaromatic and heteroaliphatic rings – do some have a better pedigree as potential drug molecules than others? , 2012 .

[48]  Peter Gedeck,et al.  Avoidance of the Ames test liability for aryl-amines via computation. , 2011, Bioorganic & medicinal chemistry.

[49]  J. Treanor,et al.  A selective prostaglandin E2 receptor subtype 2 (EP2) antagonist increases the macrophage-mediated clearance of amyloid-beta plaques. , 2015, Journal of medicinal chemistry.

[50]  Kristin L. Andrews,et al.  Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase-Glucokinase Regulatory Protein (GK-GKRP) Binding: Strategic Use of a N → S (nN → σ*S-X) Interaction for Conformational Constraint. , 2015, Journal of medicinal chemistry.

[51]  R. J. Mather,et al.  Discovery of 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (CP-810,123), a novel alpha 7 nicotinic acetylcholine receptor agonist for the treatment of cognitive disorders in schizophrenia: synthesis, SAR development, and in vivo efficacy in cognition models. , 2010, Journal of medicinal chemistry.

[52]  Julian E. Fuchs,et al.  Matched molecular pair analysis: significance and the impact of experimental uncertainty. , 2014, Journal of medicinal chemistry.

[53]  W. Guba,et al.  A Real-World Perspective on Molecular Design. , 2016, Journal of medicinal chemistry.

[54]  Sun Choi,et al.  Structure-Activity Relationships of Neplanocin A Analogues as S-Adenosylhomocysteine Hydrolase Inhibitors and Their Antiviral and Antitumor Activities. , 2015, Journal of medicinal chemistry.

[55]  R. D. Dyer,et al.  Quinazolinones and pyrido[3,4-d]pyrimidin-4-ones as orally active and specific matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis. , 2008, Journal of medicinal chemistry.

[56]  Shi Hua Ang,et al.  Discovery of tetrahydropyrazolopyrimidine carboxamide derivatives as potent and orally active antitubercular agents. , 2013, ACS medicinal chemistry letters.

[57]  Jeremy R. Duvall,et al.  Diversity-oriented synthesis yields a new drug lead for treatment of chagas disease. , 2014, ACS medicinal chemistry letters.

[58]  N. Meanwell.  Synopsis of some recent tactical application of bioisosteres in drug design. , 2011, Journal of medicinal chemistry.

[59]  Satoko Baba,et al.  Identification of a novel benzoxazolone derivative as a selective, orally active 18 kDa translocator protein (TSPO) ligand. , 2013, Journal of medicinal chemistry.

[60]  Richard D. Taylor,et al.  Rings in drugs. , 2014, Journal of medicinal chemistry.

[61]  Z. Rankovic,et al.  CNS drug design: balancing physicochemical properties for optimal brain exposure. , 2015, Journal of medicinal chemistry.

[62]  J. Bajorath,et al.  Specific chemical changes leading to consistent potency increases in structurally diverse active compounds , 2014 .

[63]  John P. Overington,et al.  The promise and peril of chemical probes. , 2015, Nature chemical biology.

[64]  María Lourdes Linares,et al.  Discovery of 3-cyclopropylmethyl-7-(4-phenylpiperidin-1-yl)-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine (JNJ-42153605): a positive allosteric modulator of the metabotropic glutamate 2 receptor. , 2012, Journal of medicinal chemistry.

[65]  C. Luo,et al.  Discovery of Substituted 1H-Pyrazolo[3,4-b]pyridine Derivatives as Potent and Selective FGFR Kinase Inhibitors. , 2016, ACS medicinal chemistry letters.

[66]  Andiliy G. Lai,et al.  Optimization of an indazole series of selective estrogen receptor degraders: Tumor regression in a tamoxifen-resistant breast cancer xenograft. , 2015, Bioorganic & medicinal chemistry letters.

[67]  Jeffrey J Sutherland,et al.  Relating molecular properties and in vitro assay results to in vivo drug disposition and toxicity outcomes. , 2012, Journal of medicinal chemistry.

[68]  V. S. Lingam,et al.  Design, Synthesis, and Pharmacological Evaluation of 5,6-Disubstituted Pyridin-2(1H)-one Derivatives as Phosphodiesterase 10A (PDE10A) Antagonists. , 2015, Journal of medicinal chemistry.

[69]  Matthew R. Lee,et al.  Quinolinone-based agonists of S1P₁: use of a N-scan SAR strategy to optimize in vitro and in vivo activity. , 2012, Bioorganic & medicinal chemistry letters.

[70]  Y. Charnay,et al.  Synthesis and structure-affinity relationships of selective high-affinity 5-HT(4) receptor antagonists: application to the design of new potential single photon emission computed tomography tracers. , 2012, Journal of medicinal chemistry.

[71]  Andrew G. Leach,et al.  Tactics to Avoid Inhibition of Cytochrome P450s , 2013 .

[72]  W Patrick Walters,et al.  Acidic and basic drugs in medicinal chemistry: a perspective. , 2014, Journal of medicinal chemistry.

[73]  Anne Mai Wassermann,et al.  Large-scale exploration of bioisosteric replacements on the basis of matched molecular pairs. , 2011, Future medicinal chemistry.

[74]  P. Hajduk,et al.  Statistical analysis of the effects of common chemical substituents on ligand potency. , 2008, Journal of Medicinal Chemistry.

[75]  Matthew L. Maddess,et al.  Overcoming mutagenicity and ion channel activity: optimization of selective spleen tyrosine kinase inhibitors. , 2015, Journal of medicinal chemistry.

[76]  Daniel J. Freeman,et al.  Discovery and optimization of a series of benzothiazole phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors. , 2011, Journal of medicinal chemistry.

[77]  Sandro Mecozzi,et al.  Cation−π Interactions in Simple Aromatics: Electrostatics Provide a Predictive Tool , 1996 .

[78]  Z. Rankovic,et al.  Drug Discovery vs hERG , 2014 .

[79]  A. Katritzky,et al.  The principles of heterocyclic chemistry , 1967 .

[80]  Michael H. Abraham,et al.  Thermodynamics of solute transfer from water to hexadecane , 1990 .

[81]  Klaus R. Liedl,et al.  Heteroaromatic π-Stacking Energy Landscapes , 2014, J. Chem. Inf. Model..

[82]  Edmund J Champness,et al.  Avoiding Missed Opportunities by Analyzing the Sensitivity of Our Decisions. , 2016, Journal of medicinal chemistry.

[83]  A. Isacchi,et al.  Identification of potent pyrazolo[4,3-h]quinazoline-3-carboxamides as multi-cyclin-dependent kinase inhibitors. , 2010, Journal of medicinal chemistry.

[84]  A. Bondi.  van der Waals Volumes and Radii , 1964 .

[85]  Andrew Leach,et al.  Quantitatively Interpreted Enhanced Inhibition of Cytochrome P450s by Heteroaromatic Rings Containing Nitrogen , 2011, J. Chem. Inf. Model..

[86]  A. Robichaud,et al.  Tricyclic thiazolopyrazole derivatives as metabotropic glutamate receptor 4 positive allosteric modulators. , 2011, Journal of medicinal chemistry.

[87]  J. Balkovec,et al.  Substituted phenyl triazoles as selective inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1. , 2011, Bioorganic & medicinal chemistry letters.

[88]  Nicholas A. Meanwell,et al.  The Influence of Bioisosteres in Drug Design: Tactical Applications to Address Developability Problems , 2014, Tactics in Contemporary Drug Design.

[89]  M. Sinz.  Avoiding PXR and CAR Activation and CYP3A4 Enzyme Induction , 2013 .

[90]  T. Comery,et al.  N-[5-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl]-4-piperidin-1-ylbutyramide (SEN78702, WYE-308775): a medicinal chemistry effort toward an α7 nicotinic acetylcholine receptor agonist preclinical candidate. , 2012, Journal of medicinal chemistry.

[91]  Spiros Liras,et al.  Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the treatment of schizophrenia. , 2009, Journal of medicinal chemistry.

[92]  A. Schiedel,et al.  Structure-activity relationships of adenine and deazaadenine derivatives as ligands for adenine receptors, a new purinergic receptor family. , 2009, Journal of medicinal chemistry.

[93]  Carrie M. Mosher,et al.  Small-molecule inhibitors of cytokine-mediated STAT1 signal transduction in β-cells with improved aqueous solubility. , 2013, Journal of medicinal chemistry.

[94]  D. Selley,et al.  Design, synthesis, and biological evaluation of 6alpha- and 6beta-N-heterocyclic substituted naltrexamine derivatives as mu opioid receptor selective antagonists. , 2009, Journal of medicinal chemistry.

[95]  Xingrong Liu,et al.  Rational use of plasma protein and tissue binding data in drug design. , 2014, Journal of medicinal chemistry.

[96]  Heike Schönherr,et al.  Profound methyl effects in drug discovery and a call for new C-H methylation reactions. , 2013, Angewandte Chemie.

[97]  D. Selley,et al.  Design, synthesis, and biological evaluation of 14-heteroaromatic-substituted naltrexone derivatives: pharmacological profile switch from mu opioid receptor selectivity to mu/kappa opioid receptor dual selectivity. , 2013, Journal of medicinal chemistry.

[98]  Ping Chen,et al.  Design, Synthesis, and Evaluation of Nonretinoid Retinol Binding Protein 4 Antagonists for the Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease , 2014, Journal of medicinal chemistry.

[99]  Keith W. Ward,et al.  Optimizing Pharmacokinetic Properties and Attaining Candidate Selection , 2012 .

[100]  Catrin Hasselgren,et al.  Explanation for main features of structure-genotoxicity relationships of aromatic amines by theoretical studies of their activation pathways in CYP1A2. , 2011, Journal of the American Chemical Society.

[101]  Paul W Smith,et al.  Lead optimization of spiropyrazolopyridones: a new and potent class of dengue virus inhibitors. , 2015, ACS medicinal chemistry letters.

[102]  P. Hipskind,et al.  Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumor cells. , 2015, Journal of medicinal chemistry.

[103]  B. Kuhn,et al.  Intramolecular hydrogen bonding in medicinal chemistry. , 2010, Journal of medicinal chemistry.

[104]  Deepak Dalvie,et al.  Strategies for a comprehensive understanding of metabolism by aldehyde oxidase , 2013, Expert opinion on drug metabolism & toxicology.

[105]  Channa K. Hattotuwagama,et al.  Lead-oriented synthesis: a new opportunity for synthetic chemistry. , 2012, Angewandte Chemie.

[106]  Karl H. Clodfelter,et al.  Structure-based identification of ureas as novel nicotinamide phosphoribosyltransferase (Nampt) inhibitors. , 2013, Journal of medicinal chemistry.

[107]  W. L. Jorgensen,et al.  Methyl effects on protein-ligand binding. , 2012, Journal of medicinal chemistry.

[108]  Sandra M. Sanabria-Bohórquez,et al.  [(11)C]MK-4232: The First Positron Emission Tomography Tracer for the Calcitonin Gene-Related Peptide Receptor. , 2013, ACS medicinal chemistry letters.

[109]  J. Macor,et al.  Synthesis and structure-activity relationships of pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones as corticotropin-releasing factor-1 receptor antagonists. , 2012, Bioorganic & medicinal chemistry letters.

[110]  J. Herbert,et al.  N-[6-(4-butanoyl-5-methyl-1H-pyrazol-1-yl)pyridazin-3-yl]-5-chloro-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-indole-3-carboxamide (SAR216471), a novel intravenous and oral, reversible, and directly acting P2Y12 antagonist. , 2014, Journal of medicinal chemistry.

[111]  K. Jacobson,et al.  Search for new purine- and ribose-modified adenosine analogues as selective agonists and antagonists at adenosine receptors. , 1995, Journal of medicinal chemistry.

[112]  S. Kitamura,et al.  Significance of aldehyde oxidase during drug development: Effects on drug metabolism, pharmacokinetics, toxicity, and efficacy. , 2015, Drug metabolism and pharmacokinetics.

[113]  J. Macor,et al.  Oxazolidinone-based allosteric modulators of mGluR5: Defining molecular switches to create a pharmacological tool box. , 2016, Bioorganic & medicinal chemistry letters.

[114]  J. McCarter,et al.  Discovery, Optimization, and in Vivo Evaluation of Benzimidazole Derivatives AM-8508 and AM-9635 as Potent and Selective PI3Kδ Inhibitors. , 2016, Journal of medicinal chemistry.

[115]  Adam Siddiqui-Jain,et al.  Discovery and SAR of 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer. , 2011, Journal of medicinal chemistry.

[116]  Charles C. Persinger,et al.  How to improve R&D productivity: the pharmaceutical industry's grand challenge , 2010, Nature Reviews Drug Discovery.

[117]  K. Pattabiraman,et al.  Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3. , 2014, Journal of medicinal chemistry.

[118]  Gregory W. Kauffman,et al.  Extraction of tacit knowledge from large ADME data sets via pairwise analysis. , 2011, Bioorganic & medicinal chemistry.

[119]  H. Bregman,et al.  The discovery of aminopyrazines as novel, potent Na(v)1.7 antagonists: hit-to-lead identification and SAR. , 2012, Bioorganic & Medicinal Chemistry Letters.

[120]  Thomas J. Raub,et al.  How hydrogen bonds impact P-glycoprotein transport and permeability. , 2012, Bioorganic & medicinal chemistry letters.

[121]  N. Meanwell.  Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety. , 2011, Chemical research in toxicology.

[122]  K. Chibale,et al.  Structure-activity relationship studies of orally active antimalarial 3,5-substituted 2-aminopyridines. , 2012, Journal of Medicinal Chemistry.

[123]  Nathan Brown,et al.  Bioisosteres in Medicinal Chemistry: BROWN:BIOISOSTERES MED CH O-BK , 2012 .