Advanced Medicinal Chemistry SLIDES B

Transcription

1 Advanced Medicinal Chemistry Filippo Minutolo CFU 3 (21 hours) SLIDES B

2 Drug likeness - ADME two contradictory physico-chemical parameters to balance: 1) aqueous solubility 2) lipid membrane permeability

3 Drug likeness - ADME important parameters 1) LogP (o LogD ph ) P = [mol] n-oct [mol] water P : partition coefficient (neutral species) D : distribution coefficient (ionizable species) D = [mol] n-oct [mol] ph(aq) P = [mol] n-oct (1-a) [mol] ph(aq) 2) PSA (o TPSA): polar surface area (Å 2 )

4 Drug likeness - ADME important parameters LogP (o LogD ph ) P : partition coefficient (neutral species) D : distribution coefficient (ionizable species) D = [mol] n-oct [mol] ph(aq) P = [mol] n-oct (1-a) [mol] ph(aq)

5 Drug likeness - ADME Lipinski rule (or rule of five ) bad absorption if: 1) molecular weight > 500 2) LogP > 5 3) H-bond donors > 5 P = [mol] n-oct [mol] water O H O N H 4) H-bond acceptors > 10 O Me O N H SNC: MW 400; LogP 3-5; H-don 0-2; H-acc 7 NO COOH!!! Adv. Drug Del. Rev. 1997, 23, 3-25.

6 Drug likeness - ADME distribution of therapeutic categories in a LogP/MW plot

7 Drug likeness - ADME Veber rule in addition to Lipinski, bad absorption if : 1) rotatable bonds (Rot) > 10 SNC: Rot 7 2) TPSA > 140Å 2 SNC: TPSA 90 Å 2 (opt. ~ 70 Å 2 ) J. Med. Chem. 2002, 45,

8 Drug likeness - ADME oral PhysChem score: Traffic Light (TL) ChemMedChem 2006, 1,

9 Drug likeness - ADME Drug Disc. Today 2006, 11,

10 Drug likeness - ADME automated ADMETox analysis

11 Drug likeness - ADME Lead-likeness Drug Disc. Today 2006, 11,

12 Fragment-based approach: low MW lead generation Drug development process Gene to Function Target to Validated Target Screen to Hit Hit to Lead Lead to Candidate Candidate to Clinical Candidate FTIH To PoC Clinical Phase II Clinical Phase III Manufacturing Launch, Marketing etc. Candidate: efficacy and safety in vivo, large-scale economic synthesis Lead: satisfactory potency and selectivity; suitable physico-chemical and pharmacokinetic properties; lack of toxicity Hit: dose-dependent good activity in preliminary screening problems with HTS: high MW hits & leads many molecules failed to pass clinical phases (those with higher chances have MW lower than average)

13 Fragment-based approach: low MW lead generation Drug development process Gene to Function Target to Validated Target Screen to Hit Hit to Lead Lead to Candidate Candidate to Clinical Candidate FTIH To PoC Clinical Phase II Clinical Phase III Manufacturing Launch, Marketing etc. frammenti attivi identification of low MW key fragments (X-ray, in silico, etc.) to be further developed towards lead generation problems of fragments: low activity (K d, K i, IC 50 ~ mm) Ligand efficiency (LE): a specific efficiency that is normalized to the non-h atoms number [normalized to molecular size]

14 Fragment-based approach: low MW lead generation Nature Chem. Biol. 2006, 2,

15 Fragment-based approach: low MW lead generation + target (e.g. protein) ligand K d K i (IC 50 ) complex DG = RTln(K)

16 Fragment-based approach: low MW lead generation DG = ΣDG i Int 1 Int 2 Int 3 Int 1 Int 2 Int 6 high MW low MW Int 5 Int 4

17 Fragment-based approach: low MW lead generation Ligand efficiency (LE): considers the number of non-h atoms (N) (LE) Dg = DG N = RTln(K) N [kcal/(mol atom)] N = number of non-h atoms R = universal gas constant = kcal/( K mol) K K i, K d, IC 50 (expressed in M, mol/l) LE represents the energetic contribution normalized to the number of non-h atoms Drug Disc. Today 2004, 9,

18 Fragment-based approach: low MW lead generation Ligand efficiency (LE): considers the number of non-h atoms (N) (LE) Dg = DG N = RTln(K) N [kcal/(mol atom)] exemples N = number of non-h atoms R = universal gas constant = kcal/( K mol) K K i, K d, IC 50 (expressed in M, mol/l) MW 500 (N ~ 36); K i = 10 nm; MW 175 (N ~ 13); K i = 1.4 mm (10 5 higher!) LE = 0.30 Drug Disc. Today 2004, 9,

19 Fragment-based approach: low MW lead generation evolution of b-secretase inhibitors peptidomimetics (low LE) IC 50, = 1.6 nm; LE = 0.19 excellent inhibitor in vitro, but it does not cross BBB fragments X-ray, low IC50, but high LE lead development J. Med. Chem. 2007, 50, e

20 Fragment-based approach: low MW lead generation evolution of b-secretase inhibitors lead development fragments X-ray, low IC50, but high LE J. Med. Chem. 2007, 50, e

21 Fragment-based approach: low MW lead generation evolution of b-secretase inhibitors J. Med. Chem. 2007, 50, e

22 Fragment-based approach: low MW lead generation evolution of b-secretase inhibitors J. Med. Chem. 2007, 50, e