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O
O
O
O
H
H
H
H
H
H
H
H
O
O
O
O
H
H
H
H
Chiral
H
H
H
H
Me
Me
Me
Me
HPLC
Me
N
N
N
N
Me
Me
Me
Me
ent
-Himbacine series
Himbacine series
Racemic lead
8 (+)-Himbacine
M
2
Ki = 4.8 nM
PAR-1 inactive
(+)-10a
R=Me
IC
50
= 150 nM
(-)-10b
R=Me
IC
50
= 1500 nM
(±)-9
R=MeIC
50
= 300 nM
Figure 2.5
Himbacine-derived PAR-1 lead. Compounds with ent-himbacine absolute
chirality showed consistently superior activity against PAR-1.
total synthesis of himbacine and several of its analogs.
62,63
Our detailed
structure-activity study of himbacine-based muscarinic antagonists has also
been published.
63
One of these racemic synthetic analogs (9), which replaces the
6-methylpiperidine motif with the corresponding methylpyridine, was totally
devoid of any antimuscarinic activity. However, this compound was identified
as a hit against PAR-1 in a later high-throughput PAR-1 assay.
2.4.4.1 Lead Optimization
In the initial phase of lead optimization, the racemic himbacine derivative 9 was
resolved using chiral HPLC. The enantiomer 10a bearing absolute chirality
opposite to that of himbacine (ent-himbacine) was found to have 10-fold more
a
nity toward PAR-1 in the binding assay than the enantiomer with natural
absolute chirality (10b). The absolute chirality was confirmed by enantiospecific
synthesis starting from (R)-but-3-yn-2-ol (Scheme 2.1).
59
The synthesis of himbacine-derived PAR-1 antagonists outlined in Scheme 2.1
employs a highly diastereoselective intramolecular Diels-Alder (IMDA) reac-
tion to generate the tricyclic intermediate 18. The protocol for the IMDA
reaction was adapted from the total synthesis of himbacine.
59,62
The synthesis
commences with commercially available (R)-but-3-yn-2-ol, which was O-pro-
tected to give 11, and subsequently elaborated to the pentynoic acid benzyl ester
12 as shown (Scheme 2.1). Esterification of 12 with dienoic acid 13 and sub-
sequent Lindlar reduction of the triple bond gave the IMDA precursor 15.
Thermal cyclization of 15 gave 66% of the required tricyclic carboxylic ester 17
after a brief in situ treatment with DBU to epimerize the stereogenic center a to
the lactone carbonyl group. Catalytic hydrogenation of 17 over platinum oxide
effected diastereospecific reduction of the double bond as well O-debenzylation
to produce the tricyclic carboxylic acid 18. The acid chloride generated from 18
was reduced to the aldehyde 19 by treatment with tributyltin hydride in the
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