Isosteresin Medicinal Chemistry Group Meeting …

1 Group Meeting Christos Mitsos Isosteres in Medicinal Chemistry 2/1/2006. Reviews Definition of Bioisosterism G. A Patani, E. J. LaVoie, Chem Rev. 1996, 3147-3176. C. G. Wermuth, in The Practice of Medicinal Chemistry , Friedman (1951): Bioisosteres are atoms or molecules that fit Academic Press 1996, pp 203-237. the broadest definition for isosteres and have the same type of biological activity. Definition of Isosterism Thornber (1979): Groups or molecules which have chemical and Langmuir (1919): Compounds or groups of atoms having the physical similarities producing broadly similar biological effects.

2 Same number of atoms and electrons Examples: N2 and CO, N2O and CO2, N3- and NCO- Grimm (1925): Hydride Displacement Law addition of Parameters affected with bioisosteric replacements hydride to an atom gives to the resulting pseudoatom' the properties of the atom with the next highest atomic number. Size, conformation, inductive and mesomeric effects, polarizability, H-bond formation capacity, pKa, solubility, hydrophobicity, reactivity, stability. Hydride Displacement Law C N O F Ne Na+. Bioisosteric replacements: Why?

3 CH NH OH FH - Greater selectivity CH2 NH2 OH2 FH2+. Less side effects CH3 NH3 OH3+ Decreased toxicity CH4 NH4+ Improved pharmacokinetics (solubility-hydrophobicity). Increased stability Erlenmeyer (1932): atoms, ions or molecules in which the Simplified synthesis peripheral layers of electrons can be consider identical. Patented lead compounds Examples: atoms in the same column of the periodic table, Cl and CN and SCN (despite having different number of atoms). Group Meeting Christos Mitsos Isosteres in Medicinal Chemistry 2/1/2006.

4 OH O. H to F replacement HN. F HN. E O N. O N S. Fluorine: similar size with hydrogen O. R. F E-SH R. most electronegative halogen HN 2'-deoxyuridylic C-F bond very stable O N E-SH. O. -O O. P. -O O. H F Cl CH3 CF3 O OH. OH CH3. HN HN. Van der 2 2 E. Waals radius O N O N S. 5-Fluorouracil R R. (antineoplastic). Molecular Thymidylate (DNA synthesis). Refractivity Inductive E-SH: Thymidylate synthase - effect F. Resonance effect O NHMe N N. F3C. Ideal replacement to study the effect of electronegativity change F.

5 Without affecting steric requirements Fluoxetine Flunarizin (Prozac) (Sibelium). antidepreessant Ca channel blocker F (or other halogens) can be placed on eacily oxidized positions to increase stability during metabolic processes O. F F CO2H. Thus, F (or other halogens when size is not critical) are CO2H. frequently place on easily oxidized aromatics N N. Methyl groups often substituted by CF3 OAc HN. Flufenisal analgesis Ciprofloxacin (Cipro). antibacterial Group Meeting Christos Mitsos Isosteres in Medicinal Chemistry 2/1/2006.

6 -OH to -NH2 or SH replacement Van der Waals IC50. X. (also C=O to C=NH or C=S) radius ( ) (nm). MeO2C CO2Et O and NH have similar sizes (but not SH) N O 140. All three bear H-bonding donor and acceptor capacities X N Me NH 160. H. Dihydropyrimidine S 17. calcium channel blockers H2N N N. H. N. N. N Halogen replacements H. X N CO2H. CN and CF3 may be used as alternative electron-withdrawing O CO2H groups instead of halogens. X = NH2, Aminopterin (Methotrexate) The two groups have comparable effects on electronics, but CN.

7 (an antimetabolite anticancer). will increase the overall hydrophilicity. X = OH, Folic acid Replacement of OH with NH2 can stabilize a different tautomer, Ring replacements especially in the case of heterocyclic systems Sulfonamide antebacterials: phenyl Group may be replaced by many heterocycclic aromatics to give active compounds N O N OH O O N. H S Ar N Ar =. more stable H N N. H2N. Sulfapyridine Sulfapyrazine S N. N NH N NH2. H N N. more stable Sulfathiazole Sulfapyrimidine Group Meeting Christos Mitsos Isosteres in Medicinal Chemistry 2/1/2006.

8 COOH replacements Peptide surrogates O O O O O Peptides are characterized by diminished bioavailability O OH CN S. N N N R when administered orally. H H H. OH Replacement of the sensitive amide bond by various groups hydroxamic acylcyanamide sulfonimide can increase their stability. (strong chelating agents) (similar acidities). O O O O O. P OH S S R2 R2. OH OH NHR O O. H H. N N. phosphonate sulfonate sulfonamide O N. (more acidic; (less acidic) O R O. ionized at physiological pH) R1 R1. Ester N-alkylation N N O N N O.

9 N OH O R2 R2. N R2 O. N O H. H H H H. N N N N. N N. tetrazole hydroxyisoxazole oxadiazolone H. O H O. R1 O R1. R1. Amide to double bond Azapeptide Carboxyl Group may be replaced in order to alter acidity, or modify lipophilicity without affecting pKa Tetrazoles have comparable pK's with carboxylic acids, but greater R2 R2. S O. lipophilicity H H. N N. N N. H H. O O. Cl R1 R1. N Thioamide Dehydroaminoacid HO. N N N. HN N Losartan (antihypypertensive). CH3. Group Meeting Christos Mitsos Isosteres in Medicinal Chemistry 2/1/2006.

10 Preparation of tetrazoles BocHN BocHN. H. N TMSN3, DEAD N. Ph Ph R O PPh3, THF O. N CN Ph3P CN. N. -N N. N HN3 R N BocHN BocHN. CN NaOH;. N N N. R base, HN N Ph Ph N HCl N. R N N HN N. N. N- N N J. Med. Chem 2000, 43, 488. N N. N Cl PMB. CN MeO Cl N ClCH2C(OEt)3. H N. NaN3, NH4Cl NH2 NaN3, AcOH EtO N N. N N. PMB. DMF, 90 oC. PhtHN CO2Me PhtHN CO2Me Tet Lett 1998, 39, 3367. O CO2H O OSiR3 N N. SiCl4, NaN3 N. O N NH2 N N. H MeCN, reflux SiR3. SiR3. HN N. N N NH H2O. N N. Tomudex analogues N N. N. Tet Lett 1997, 38, 1257.