3 research outputs found
Process Development of the Soft Histone Deacetylate Enzyme Inhibitor SHP-141: Acylation of Methyl Paraben and Suberyl Hydroxamic Acid Formation
SHP-141 (<b>1</b>) is a hydroxamic acid-based inhibitor of
histone deacetylase enzymes which is under development for the treatment
of cutaneous T-cell lymphoma. The original synthesis of <b>1</b> involved five synthetic steps beginning with suberic acid monomethyl
ester. Final deprotection of the <i>O</i>-benzyl hydroxamate
moiety using hydrogen and palladium catalyst mandated the use of metal
scavengers to reduce palladium levels to within International Council
for Harmonisation (ICH) guidance. Owing to the sensitivity of <b>1</b> toward self-condensation and the potential for N–O
bond cleavage under hydrogenolytic conditions, we developed an alternative
route to <b>1</b> which avoids Pd-mediated hydrogenation and
prolonged metal scavenger treatment. This two-step process employs
readily available suberic acid and methyl paraben and has successfully
delivered multiple kilograms of <b>1</b> for clinical use. Importantly,
crude <b>1</b> was stabilized for recrystallization in acetonitrile
(ACN) solution by the addition of 0.1% citric acid and 4% water. Additionally,
the filtration and drying of suitably sized aggregates of <b>1</b> with high purity (100 area%) was accomplished via temperature cycling
of the <b>1</b>/ACN solution
Process Development and Synthesis of Birinapant: Large Scale Preparation and Acid-Mediated Dimerization of the Key Indole Intermediate
Birinapant/TL32711
(<b>1</b>) is a novel bivalent antagonist
of the inhibitor of apoptosis (IAP) family of proteins which is currently
in clinical development for the treatment of cancer and hepatitis
B virus (HBV) infection. In this report, we present a detailed description
of the <b>1</b> drug substance synthesis used to support our
ongoing clinical studies. Key transformations in this process included
the development of a scalable, high-yielding route to acyl indole <b>14</b> as well as a two-step dimerization/oxidation of indole <b>19</b> that afforded biindole <b>21</b> in excellent yield
and purity (70% yield, 2 steps; >95 area% purity by HPLC analysis).
In addition, partial defluorination of <b>21</b> was observed
following hydrogen-mediated benzyloxycarbonyl (Cbz) protective group
removal which was obviated by the use of HBr/HOAc for this transformation.
The use of commercially available amino acid derivatives afforded
related impurities which proved difficult to purge in subsequent steps.
Thus, defining the impurity specification for these reagents was critical
to providing <b>1</b> drug substance of >99 area% chemical
purity.
Using this process, we have successfully prepared <b>1</b> drug
substance multiple times on >500-g-scale in support of our clinical
development program
Birinapant, a Smac-Mimetic with Improved Tolerability for the Treatment of Solid Tumors and Hematological Malignancies
Birinapant (<b>1</b>) is a
second-generation bivalent antagonist
of IAP proteins that is currently undergoing clinical development
for the treatment of cancer. Using a range of assays that evaluated
cIAP1 stability and oligomeric state, we demonstrated that <b>1</b> stabilized the cIAP1-BUCR (BIR3-UBA-CARD-RING) dimer and promoted
autoubiquitylation of cIAP1 in vitro. Smac-mimetic <b>1</b>-induced
loss of cIAPs correlated with inhibition of TNF-mediated NF-κB
activation, caspase activation, and tumor cell killing. Many first-generation
Smac-mimetics such as compound <b>A</b> (<b>2</b>) were
poorly tolerated. Notably, animals that lack functional cIAP1, cIAP2,
and XIAP are not viable, and <b>2</b> mimicked features of triple
IAP knockout cells in vitro. The improved tolerability of <b>1</b> was associated with (i) decreased potency against cIAP2 and affinity
for XIAP BIR3 and (ii) decreased ability to inhibit XIAP-dependent
signaling pathways. The P<sub>2</sub>′ position of <b>1</b> was critical to this differential activity, and this improved tolerability
has allowed <b>1</b> to proceed into clinical studies