irreversible inhibitors of erbb-family of kinases_gsk
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Irreversible Inhibitors of ErbB-family of kinasesGlaxoSmithKline (2002-2004)Robert D Hubbard, Ph.D.
GlaxoSmithKline (2002-2004)Irreversible Inhibitors of ErbB-family
N
N
HN
O
NHS
OO Cl
OF
TykerbTM
Reversible EGFR/ ErbB-2BT474 Proliferation (IC50,nM) = 100
N
NS
HN
NH
HCl
OF
Irreversible EGFR/ ErbB-2EGFR modification @ 3hr = 47%
BT474 Proliferation (IC50,nM) = 94
Explore the SAR on substituted pyrrolidines: modification, cellular activityPNAS 2008, 105,2773
N
NS
HN Cl
OF
H
SCys797 Structure in ErbB-4
A. Waterson, D. Uehling.
Proposed mechanism of modification requires a basic pyrrolidine crucial
Analog BT474 (IC50, nM)
EGFR mod. @ 3 hr (%)
R = H 94 47R = -(CH2)2OMe
110 19
R = -SO2Me 650 0R = -C(O)OMe 1700 0 BMCL 2008, 18, 5738
N
NS
HN
N
HCl
OF
R
TykerbTM (green)Thienopyrimidine (red)
Substituted Carbamoyl-pyrrolidinesProvided a balance of activity and minimized EGFR modification
N
NS
HN
NH
Cl
OF
N
NS
HN
NH
Cl
OF
OHN
O
N
NS
HN
NH
Cl
OF
ON
O
N
NS
HN
NH
Cl
OF
ON
O
O
ON
O
R1
R2
N
NS
HN
BrN
Cl
OF
ON
O
R1
R2
N
HO
BOC1. NaH, then R1R2COCl
2. Sonogashira Coupling3. TFA
BOC
CO2MeN
HO
BOC
Corey-Fuchs
BMCL 2009, 19, 21.
SAR comments: Potency: Et > Dimethyl > MorpholinePK: Morpholine ~ Dimethyl > EtModification of EGFR @ 3hr: < 15%
From Laulimalide total synthesis (Stanford)Modified Seyferth-Gilbert Reaction
OH
HO
OTBS
OTBSO
H
1. MOMCl, DIEA, CH2Cl2, RT (99%)2. (a) BH3-DMS, cyclohexene, THF(b) H2O2, 3 M NaOH, EtOH (87%)
3. Dess-Martin, NaHCO3, CH2Cl2, H2O (85%)O
H
MOMO
OTBS
OTBSO
H
O
4. K2CO3, MeOH (76%)
5. n-BuLi, ClCO2Me, THF,-78C (79%, 86% BORSM)
OH
MOMO
OTBS
OTBSO
H
CO2Me
6. HF-pyridine, THF, RT (98%)
7. LiOH, THF, water, RT (76%)O
H
MOMO
OH
OHO
H
CO2H
8. 2,4,6-trichlorobenzoyl chloride,Et3N, DMAP, benzene, RT (55%)
O
O
OHO
H
OMOMH
OH
O
OO
OHHHO
H
OHO
H
Laulimalide
O
N2
PO
O
O
JACS 2002, 124, 4956.
Synthesis of all possible diastereomers (4-OH proline)
N
HO
CO2Me
BOC
1. TBDPSCl, Imid2. LiBH4, THF
3. Dess-Martin, CH2Cl2,water
N
TBDPSO
CHO
BOC
P
N2
OO
K2CO3, MeOH, RT N
TBDPSO
BOC
4. 5. TBAF, THF
(R)
N(S)
HO
BOC
7. Ph3P, DIAD, pNO2-PhCO2H
(S)
N(S)
HO
BOC
O O
NH
HO
CO2Me1. Ac2O, AcOH
NO
ORR = -Ac
then HCl, refluxNH
HO
CO2H2. SOCl2, MeOH
3. BOC2, TEA, DMAP N
HO
CO2Me
BOC
4. TBDPSCl, Imid
5. DIBAL-H, -78C, then MeOH
N
TBDPSO
CHO
BOC
OP
N2
OO
O
N
TBDPSO
BOC
6. TBAF, THF(R)
N(R)
HO
BOC
7. Ph3P, DIAD, pNO2-PhCO2H
(S)
N(R)
HO
BOC
BMCL 2009, 19, 21.
SAR analysis of four possible stereoisomers of the pyrrolidinyl-carbamate – SAR consistent for all carbamates
Analog
BT474 (IC50, nM) 30 50 130 10
Ms PO PK (mM*hr) 1.5 ~ 0.3-0.5 low low
N
NS
HN
R
Cl
OF
NH
ON
O NH
ON
ONH
ON
ONH
ON
O
N CO2Me
HO
BOC
(-)-Aldrich
N CO2Me
HO
BOC(+)-not available, crazy expensive
Letter from Aldrich??
GSK – Summary
• Decoupled EGFR modification from cellular potency
• SAR of cellular activity, PK, and modification dependent on the stereochemistry of the substituents on the pyrrolidine ring
• Project was terminated due to concerns of irreversible inhibition of target kinases.
• T790M mutation requires irreversible inhibition for potent activity (PNAS 2008, 105, 2070).