Chap 7. Solubility Lee, Sang-Hwi Solubility Fundamentals Maximum dissolved concentration under given condition Determinant of intestinal absorption and oral BA. Increased by adding ionizable groups or reducing Log P and M.W. etc. Salt forms increase dissolution rate: How much vs How fast Solubility Physical state Solvents Methods of measurement Methods of measurement pKa Size Lipophilicity Crystal lattice energy Compound Structure Banergee et al. Log S=0.8-logP-0.01(MP-25) Log P 1unit () Solubility 10x () MP 100 o C () Effects of Solubility Low solubility Limits absorption and causes low oral Bioavailability Hampered toxicity study at higher dose Non-linear PK profiles (2 nd peak phenomena) YH-439 Low oral BA (0.9~4.0% in rat) Poor aq. solubility LY295501 Minimum Acceptable Solubility Maximum Absorbable Dose mg/mL pH 6.5 Intestinal absorption rate constant min-1 Small intestine water volume (~250mL) Small intestine transit time (~270min) SolubilityPermeability In drug discovery, solubility > 0.1 mg/mL Formulation often can help to increase the solubility of insoluble compounds. maximum absorption of a compound with minimal solubility depends on high permeability and potency. Criteria for human oral absorption Biopharmaceutics classification System Low Formulation Prodrug Risky and Costly No in vitro/in vivo correlation Compounds in the same BCS class tend to have behave in similar manner With regard to absorption and can follow the same regulatory approval process with regard to in vitro / in vivo correlation experiments. Idea (Oral) Solubility and permeability Lipinsky et al. Solubility is much larger issue for drug discovery than is permeability Permeability tends to vary over a more narrow range than does solubility - Low permeability (x 50 fold) High permeability (0.001~0.05min -1 ) - Low solubility (x fold) High solubility (0.1g/mL~100mg/mL) Advanced Drug Delivery Rev , 3 Pharm Sci & Tech. Today , 387 Eur. J. Pharm. Sci. 1998, 7, 1 7.3. Effects of Physiology on Solubility and Absorption Physiology of the Gastrointestinal Tract Species difference in Gastrointestinal Tract GI tract pH can be different among the species - Rats, Humans: Good acid secretor - Cats, Dogs: secrete less acid -10- MedChem approaches Structure Modification Strategies to improve Solubility Add ionizable groups Reduce Log P Add hydrogen bonding Reduce M.W. Out-of-plane substitution to reduce crustal packing Construct a prodrug Structure modification Add Inonizable Groups Artemisinin derivatives Compounds with an ionizable functional group will be charged in pH buffers Introduction of a Basic amine or a Carboxylic acid J. Med. Chem. 2000, 43, Anti-malarial agents (natural) - Fast action, low toxicity, high activity against Both drug resistant & drug sensitive malaria - Low aq. Solubility, Low oil solubility - High recrudescence rate Artemisinin 1 (Qinghaosu) Oil soluble (2b) Water soluble (2c) - aq. Solution unstable Approved in 1987 Etheral linkage - More stable - but No anti-malarial efficacy Introduction of amino groups Introduction of OH groups Add Inonizable Groups DNA minor groove alkylating agents Cyclopropylindole class - Extremely potent cytotoxins - Alkylate DNA in a sequence selectively. at adenine N3-sites in the minor groove. - CC-1065(1) shows delayed toxicity in animal - Simpler analogs dont shows delayed toxicity. (5, 6, 7) Minimum potent pharmacophore J. Med. Chem. 1999, 42, 649 Add Inonizable Groups DNA minor groove alkylating agents EDG & Cytotoxicity 5-, 6-OR solubilizing NMe 2 group Lower solubility of 7-OR could be due to difference in crystal packing J. Med. Chem. 1999, 42, 649 Add Inonizable Groups Crystophycin analogs Crytophycin 1 - a potent anti-microtubule agent isolated from cyanobacteria - Poor solubility Crytophycin 8 (Chlohydrin) - More efficacious than Crytophycin 1 Adding a basic nitrogen as an ionizaion center - Good potency - Good aq. solubility J. Med. Chem. 2003, 46, 2985 Reducing Log P HIV inhibitor Pharm. Rev Hydroxy ethylene dipeptide isostere series - Highly lipophilic - Poorly soluble - Poor BA Adding a basic nitrogen - Pyridine analog : Indinavir (MK-639, L-735,524) Transition state mimics Add Hydrogen Bond Anti-AIDS agents J. Med. Chem. 2004, 47, 756 Hydrogen Bond Donor Acceptor : OH, NH 2 Introduction of polar group also can serve as a linker with other polar moieties to form pro-drug. - DCK (1), EC 50 = 2.56 x M - 4-Methyl DCK (2), EC 50 = 1.83 x M (Preclinical candidate) : Low solubility, Poor BA. Key pharmacophore 3-, 6-position polar group Add Hydrogen Bond Anti-AIDS agents CompoundsLog P c3.04 4c3.65 5c3.06 Add Hydrogen Bond Anti-AIDS agents Polar group additional solubility Oral BA But, Solubility oral BA (2 vs 4c vs 5c) MoA . High systemic CL 1 st pass effect oral BA 3A4 phase I main Large Vd Add Hydrogen Bond Soluble Nystatin analogs Polyene macrolide - Antifungal agents: Fungicidal MoA - Low Solubility, Significant human toxicity - Very non-polar - Hydrophobic interaction with sterol within the cell membrane - Orienting Polyol part toward the internal aqueous channel C-31, C-33 OH - Solubility 2000 - But No anti-fungal activity J. Med. Chem. 2006, 49, 2431 Add Polar Group Soluble Epoxide hydrolase J. Med. Chem. 2004, 47, 2110 Soluble Epoxide hydrolase (sEH) - Involved in metabolism of endogeneous chemical mediator - Control of blood pressure and inflammation 1,3-disubstituted urea analogs - Active in vitro, in vivo - poor Solubility in either water and lipid in vivo efficacy formulation IC 50 Solubility 0.10M 0.62mg/mL Polar groups were incorporated at least 5 atoms (~7.5) with no loss of activity - Lipophilic inhibitor polar group . - Water shell around the polar group hinder and reduce the active site binding Distal positioning of polar group and making new HB interaction Add Polar Group Soluble Epoxide hydrolase Add Polar Group FXR inhibitor J. Med. Chem. 2010, ASAP FXR - Expressed in the liver, kidney, intestine - activated by bile acid (CDCA, CA) - maintain cholesterol and bile acid homeostasis - regulates the expression of a number of genes - involved in TG synthesis and lipogenesis - Highly lipophilic, clogP=5.30 Add Polar Group FXR inhibitor Metabolic stability enhancement by F Solubility enhancement by Polar group (Solvent exposure part) Add Polar Group FXR inhibitor Add Polar Group FXR inhibitor Add Polar Group VEGFR2 inhibitor J. Med. Chem. 2006, 49, 2144 VEGFR2 (KDR) - Involved in multiple process of angiogenesis - PoP in clinic: Colorectal patient Bevacizumab(mAb) patient survival Better PK profiles !! Polar group attachment To solvent exposure part Add Polar Group VEGFR2 inhibitor Add Polar Group VEGFR2 inhibitor Out-of-plane substitution. NMDA anatgonist NMDA antagonist - Glycine Glutamic acid ligand - Overstimulation of NMDA receptor: Stroke, AD, PD, Huntingtons disease etc. - Glycine binding site anatagonist side effect glutamic acid antagonist - but, in vivo Acidic property make to difficult to BBB penetration Development stop In vitro activity (good) In vivo activity (Poor) - t1/2 40 fold enhancement disruption of crystal packing