The Importance of Fluorine in the Design of BACE Inhibitors .


22 views
Uploaded on:
Category: Sales / Marketing
Description
KaoHsiung Medical School KaoHsiung, Taiwan December 14, 2009. The Importance of Fluorine in the Design of BACE Inhibitors. James R. McCarthy. 14,000,000. 12,000,000. 10,000,000. 8,000,000. NUMBER OF VICTIMS. 6,000,000. 4,000,000. 2,000,000. 0. 1900. 1910. 1920. 1930. 1940.
Transcripts
Slide 1

KaoHsiung Medical School KaoHsiung, Taiwan December 14, 2009 The Importance of Fluorine in the Design of BACE Inhibitors James R. McCarthy

Slide 2

14,000,000 12,000,000 10,000,000 8,000,000 NUMBER OF VICTIMS 6,000,000 4,000,000 2,000,000 0 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 2020 2030 2040 2050 YEARS Age 65-74 Years Age 75-84 Years Age 85+ Years Prevalence of Alzheimer\'s Disease (AD) (By decades in U.S.A. from 1900-2050)

Slide 3

Contrast Between the Healthy Brain and the Advanced AD Brain Ventricle Hippocampus

Slide 4

Two fundamental obsessive signs of AD: neuritic plaques and neurofibrillary tangles Neurtic plaques Neurofibrillary tangles Largely A b peptide Hyperphosphorylated tau More particular to AD Found in numerous neurological issue

Slide 5

BACE ( b - SECRETASE) HYPOTHESIS Blocking the main cleavage of APP by b - secretase will restrict the substrate for g - secretase and decrease A b peptide creation. sAPP b Amyloid Precursor Protein KPI OX NH 2 + NH 2 + b - amyloid (A b 38-49 ) (b - secretase) First step + CLEARANCE Diffuse Primitive (Immature) g - secretase COO - COO - Classic (Typical) C99 (b - CTF) Compact (Burnt-out) - Lilly Confidential BACE Clark and Trojanowski, 2000, Neurodegenerative Dementias, p151.

Slide 6

Common isosteres that copy the tetrahedral middle of the road of amide security hydrolysis as catalyzed by aspartyl proteases (TSAs): N-terminal Central center C-terminal P1\' P2 P1 P3 P2\' Ethanolamines Hydroxyethylenes BACE ( b - APP Cleaving Enzyme) is a film bound aspartyl protease Aspartyl protease system of activity

Slide 7

BACE1, an Aspartyl Protease, co-takes shape with a substrate mimetic inhibitor OM99-2 (Tang, Hong et. al., Science, 2000, 290 , 150-153) The dynamic site of BACE is characterized by OM99-2, containing the hydroxyethylene center (Leu*Ala) K i = 1.6 nM

Slide 8

OM99-2/BACE1 Interactions (K i = 1.6 nM)

Slide 9

Hippocampus Vehicle 0.5 treated 0.4 67% 60% 0.3 *** Hippocampus A b (x-40 ) (ng/gm) ** 0.2 0.1 0.0 mdr_KO PO mdr_KO SQ A Novel Sulfone That Is Efficacious in Pgp Transporter Deficient Mice mcaFRET IC 50 = 0.4 nM A b IC 50 = 1 nM Mouse microsome digestion system = 90% Rat microsome metabolisn = 87% Caco2 = 3%

Slide 10

Polar P2 Binding Groups Give Potent Inhibitors That Do Not Penetrate the Brain of Wild Type Mice

Slide 11

Physical properties of BACE inhibitors are key for cerebrum entrance For a sensible possibility of compound intersection Blood-Brain Barrier (BBB), taking after physical properties are critical: cLog P > 2 and < 5 PSA < 85 Å 2 MW < 500 Caco-2 > 200 nM/sec cpKa < 8 Van der Waterbeemd, H.; Camenisch, G.; Folkers, G.; Chretien, J.R.; Raevsky, O.A. Estimation of blood-cerebrum boundary intersection of medications Using atomic size and shape and H-holding descriptors. J. Medicate Targeting , 1998 , 6(2) , 151-165 Kelder, J.; Grootenhuis, P.D.J.; Bayada, D.M.; Delbressine, L.P.C.; Ploemen, J.- P. Polar atomic surface as an overwhelming determinant For oral assimilation and cerebrum entrance of medications. Pharm. Res. , 1999 , 16(10) , 1514-1519

Slide 12

Designing Efficacious BACE Inhibitors Which pockets are essential to involve? Use coordinated SAR to characterize restricting open doors.

Slide 13

Strategy: Design BACE inhibitors with clogP > 2 and < 5 PSA < 85 MW < 500 cpKa < 8 Replace polar N-terminal gatherings with littler gatherings Retain power through novel C-terminal rings to build inflexibility R = Me BACE1 IC 50 = 80 M BACE1 IC 50 > 100 M BACE1 IC 50 =2 nM

Slide 14

Difluorophenyl at P1 is 5 times more intense versus phenyl Increase in power reliable with van der Waals Forces between the fluorines and the surface of the protein. (Will be delineated with a gem structure)

Slide 15

BACE1 IC 50 = 20 nM 9.2 Hz 9.5Hz 1.8Hz 8 9 7 6 unsubstituted 9.2 Hz 6.5Hz 3.05 Hz 7 9 8 6 Extreme coupling constants for compound 1 demonstrate a more inflexible arrangement structure 7 8 1 BACE1 IC 50 = 926 nM 9 2

Slide 16

Cyclization Strategies BACE1 IC 50 = 20 nM • 5 and 6-membered rings display ideal authoritative to BACE1 (by DOCKing tests) BACE1 IC 50 = 0.35nM A b IC 50 = 5.7nM

Slide 17

Elimination of polar gathering at P2 & diminish in MW smallly affect BBB infiltration P2\' P3 P1 P3 P1 2 3 1 BACE1 IC 50 = 0.4 nM A b IC 50 = 5.7 nM B/P = 0.02 MW = 553 PSA = 132 BACE1 IC 50 = 0.5 nM A b IC 50 = 1.5 nM B/P = 0.02 MW = 580 PSA = 127 BACE1 IC 50 =80000 nM B/P = 0.06 MW = 312 PSA = 61 Hypothesis: Basicity of nitrogen on compound 3 (cpKa = 9.5) prevents blood mind hindrance entrance

Slide 18

Optimization system Di-hub gatherings are required to fill S1\' and S2\' pockets Addition of hydrophobic P1\' & P2\' bunches prompted the outline of littler less polar inhibitors S1\' take BACE1 IC 50 = 0.35 nM S2\' stash

Slide 19

Introduce P2\' gathering to enhance intensity Both structures exist in arrangement

Slide 20

Enhance inhibitor preorganization and unbending nature by means of stereoelectronic impacts

Slide 21

Synthesis of 3-Alkyl-2-Alkoxy morpholine BACE inhibitors X-beam gem structure unequivocally settled the stereochemistry at all three chiral focuses

Slide 22

Synthesis of 3-Alkyl-2-Alkoxy Morpholines (cont)

Slide 23

Alternative Synthesis of 3-Alkyl-2-Alkoxy morpholine BACE inhibitors

Slide 24

BACE IC 50 = 1320 nM BACE IC 50 = 222 nM BACE IC 50 = 306 nM B/P 0.07 (Brain to Plasma presentation proportion) B/P 0.42 B/P 0.48 Progression of the SAR: P2\'/P1\' on morpholine 2434074 BACE IC 50 = 77 nM A b IC 50 = 91 nM MW =414 BACE IC 50 = 2800 nM A b IC 50 = 2160 nM B/P 0.38 Morpholine ring diminished pKa & gave anomeric impact Introduction of P1\' methyl expanded power

Slide 25

P1\' pivotal P2\' cLogP = 2.4 PSA = 70 A 2 MW = 414 cpKa = 7 Caco-2 perm ~ 300 nM/sec Anomeric impact favors hub P2\' O-neopentyl 2434074 shows craved physical properties for a CNS medicate o

Slide 26

Pharmacokinetics of 2434074 in wild sort mice indicates negligible presentation after oral organization (10 mg/kg) s.c 2434074

Slide 27

rodent A P+O B O-dealkylated B A control parent Rat hepatocyte digestion system for 2434074 Metabolism prevalently on P2\' neopentyl amass

Slide 28

Approach to decline digestion system at P2\' Mouse hepatic microsomal investigations demonstrate that most digestion system is focused on the P2\' position Introduction of fluorine at P2\'

Slide 29

Fluorinated alcohols intended for connection at the P2\' site on the morpholine inhibitors

Slide 30

Routes to Fluoro-Neopentyl Alcohols Represented by the Syntheses of 3-Fluoro-2-fluoromethyl-2-methyl-propan-1-ol ( 3 )

Slide 31

Synthesis of (R) and (S)- 3,3-difluorocyclohexanemethanol

Slide 32

Representative blend of P2\' fluorinated neopentyl BACE inhibitor

Slide 33

Approach to reduction digestion system at P2\' 2434074 The bis (difluoroMe) simple of 2434074 keeps up strength with diminished digestion system

Slide 34

Approach to abatement digestion system at P2\' Introduction of oxygen or fluorine on cyclic P2\'substituents prompt diminished digestion system additionally diminished action

Slide 35

S2\' Iterative Docking and X-beam Studies for presentation of fluorine on P2\' Cyclohexyl SAR indicated polar gatherings not endured in S2\' take Docking recommended 3-cyclohexyl position may permit option of metabolic balancing out difluoro substitution Subsequent x-beam structure (yellow) checked this discovering {

Slide 36

Significant distinction in action of the two enantiomers mcaFRET IC 50 = 45 nM A b IC 50 = 67 nM Rat surrogate digestion system: 49% PSA = 72.9 cLogP = 2.6 MW = 475 Caco-2 = 24.2 mcaFRET IC 50 = 280 nM A b IC 50 = 473 nM Rat surrogate digestion system: half

Slide 37

X-beam precious stone structure of 1 co-solidified with BACE 1

Slide 38

X-beam gem structure of 1 co-solidified with BACE 1

Slide 39

Summary Structure-based medication plan was used to acquire drugable BACE inhibitors The significance of fluorine in the plan of the BACE inhibitors was appeared to be two-overlay: - Fluorines substituted on the meta - positions of P1 phenyl aggregate brought about an expansion in intensity by means of van der Waals compels between the surface of the protein and the fluorines. - The expansion of the aliphatic fluorines on the 3-position of the P2\' cyclohexyl gather brought about diminished digestion system. The precious stone structure demonstrates that the fluorines are arranged at the edge of the pocket and are not meddling with associations of the cyclohexyl amass with amino acids in the S2\' stash.

Slide 40

Neuroscience Yuan Su Binhui Ni Len Boggs Zhixiang Yang Patty Gonzalez-Dewhitt Patrick May Bruce Gitter Dan Czilli Sheila Little Ed Johnstone Ginnie Yang Jiangqing Huang Xiyun Chai Tingui Yin Yuan Tu Kelly Bales Steven Paul Suizhen Lin Carrie Jones Beth Hoffman Lijun Yang Harlan Shannon Chemistry Dave Bender Patrick Hahn Todd Kohn Dawn Brooks Chris Rito Allie Tripp Shui-Hui Chen Yvonne Yip Deqi Guo Jason Lamar Jingdan Hu Cindy Cwi Dave Timm Jim Copp Michael Wiley Timothy Shepherd Rob Dally Bob Murff Dave Mitchell Mike Shapiro Teddy Zartler Richard Harper Fuyao Zhang Fred Bruns Jon Erickson Kenn Henry Jayana Lineswala Brian Warson Scott Sheehan Tim Durham Jim Toth Chemistry Howard Broughton Jose Alfredo Martin Alicia Marcos Isabel Rojo Charo Gonzalez Ana Belen Bueno Fatima Iradier Alicia Torrado Javier Agejas Gema Sanz ADME/Toxicology/Biopharm Terry Lindstrom Mike Clay Kate Hillgren Vasu Vasudevan Tim Ryan Yu-hua Hui Helen Huang Tom Raub Statistician Viswanath Devanarayan DCSG José Francisco Soriano Juan Ramón Rodríguez José Miguel Mínguez (MPC) Chin Liu Gema Ruano PPM Stan Sorgen Scott Li

Recommended
View more...