pletely to afford a 44:56 mixture of trans-13 and cis-13 in
43% combined yield.11b
Table 1. FTase Inhibition Dataa and Pharmacokinetic Datab in
The influence of the methyl group at the 2-position of the
imidazole ring on the cis/trans distribution in the products
can be rationalized by consideration of transition states for
the iminium ion cylization. The favored transition state A
(Figure 1), which would lead to trans-products, is preferred
Dogs Following Combination Oral Dosing at 1 mpk
compd
IC50 (nM)a
t1/2 (h)
Cmax (µM)
AUC rel 1d
1
2
8440
3840
3800
0.79 ( 0.2c 2.98 ( 1.3c
1.00
4.16
2.43
0.76
trans-2
trans-13
cis-13
10.6
1.59
1.34
0.93
13.3
5.5
a Concentration of compound required to reduce the FTase-catalyzed
incorporation of [3H]FPP into recombinant human K-Ras by 50% (see ref
13). b Compounds were administered orally to two dogs as mixtures with
10 other compounds, each at 1 mg/kg, with compound 1 included as an
internal reference. Plasma extracts were analyzed by LC/MS/MS, and
reported data are the average of two dogs unless otherwise indicated (see
ref 16). c Mean data from 19 experiments, in good agreement with single
compound administration data. d The ratio of the compound’s average AUC
to that of the internal standard 1 from the same experiment.
tion for this is that the required enzyme-bound conformation
is precluded by the trans and cis ring constraints.14 That both
trans-13 (presumably a diequatorial half-chair)15 and cis-13
(presumably an axial-equatorial half-chair) are considerably
less potent than the unconstrained system 1 implies that the
cyanophenyl and piperazinone groups of 1 are required to
align themselves perpandicular to the imidazole ring, in either
an anti relative orientation or a syn orientation, on binding
to the enzyme active site. These putative bound conforma-
tions of 1 would correspond to the higher energy trans-13
diaxial half-chair and cis-13 diaxial boat, respectively.15
Alternatively, the ethano-bridge may experience destabilizing
intermolecular interactions with residues in the enzyme active
site. It is also possible that both intramolecular conforma-
tional and intermolecular steric effects may contribute
simultaneously to the decrease in inhibitory activity. In
contrast, the pharmacokinetic behavior of compounds after
oral dosing to dogs was significantly improved by the
presence of the tetrahydroimidazo[1,5-a]pyridine ring con-
straint.14,16 Although FTI 1 had less than a 1 h half-life,
compounds trans-2 and trans-13 exhibited half-lives greater
than 10 h and were well absorbed (Table 1). This may be
the result of a steric blockade of potential metabolic sites in
the parent molecule 1.4,17
Figure 1. Chair transition state for the formation of trans-5,6,7,8-
tetrahydroimidazo[1,5-a]pyridines showing A(1,3)-strain interaction
for R * H.
relative to alternative boat conformers and chair conformers
with axial substituents. However, the addition of a methyl
group to the imidazole ring (13, R ) Me) exerts a significant
conformational bias due to an A(1,3)-strain interaction12 with
the 4-cyanophenyl group. Consequently, alternative transition
states would be favored.
The conformationally constrained FTIs were found to have
diminished FTase inhibitory activity13 relative to that of the
unconstrained compound 1 (Table 1). One possible explana-
(11) (a) Representative procedure: To a solution of aldehyde 10a (824
mg, 3.45 mmol) and amine 11 (726 mg, 3.45 mmol) in 10 mL of anhydrous
chlorobenzene under argon was added MgSO4 (1.00 g, 8.3 mmol). The
reaction was heated to reflux for 1.5 h, cooled to room temperature, diluted
with dichloromethane (300 mL), filtered, and concentrated in vacuo.
Purification by flash chromatography (6 × 15 cm silica gel, 40 f 80%
acetone/dichloromethane) provided 12 (276 mg, 19%) and trans-2 (455 mg,
31%), both as pale yellow foams. (b) Data for compounds: trans-2, 1H
NMR (400 MHz, CDCl3) δ 7.68 (d, J ) 7.1 Hz, 2H), 7.32-7.37 (m, 2H),
7.22-7.28 (m, 3H), 7.22 (d, J ) 7 Hz, 2H), 7.14 (d, J ) 3.3 Hz, 1H), 5.20
(dd, J ) 7.9 and 4.4 Hz, 1H), 4.09 (dd, J ) 8.6 and 5.1 Hz, 1H), 3.73 (m,
1H), 3.63 (m, 1H), 3.63 (d, J ) 16.2 Hz, 1H), 3.49 (d, J ) 16.2 Hz, 1 H),
3.03 (m, 1H), 2.94 (m, 1H), 2.52 (m, 1H), 2.07 (m, 1H), 1.80-1.96 (m,
2H); m/z (FAB+) 432.3 (MH+). 12: 1H NMR (400 MHz, CDCl3) δ 7.67
(d, J ) 7.3 Hz, 2H), 7.30-7.36 (m, 2H), 7.21-7.25 (m, 2H), 7.17 (d, J )
8.4 Hz, 2H), 7.07 (d, J ) 1.3 Hz, 1H), 6.50 (d, J ) 1.3 Hz, 1H), 5.21 (dd,
J ) 7.8 and 5.1 Hz, 1H), 4.07 (dd, J ) 7.9 and 5.1 Hz, 1H), 3.74 (m, 1H),
3.68 (m, 1H), 3.60 (s, 2H), 3.46 (m, 1H), 3.07 (m, 1H), 2.58 (m, 1H), 2.13
(m, 1H), 1.90-2.05 (m, 2H); m/z (FAB+) 432.3 (MH+). trans-13: 1H NMR
(400 MHz, CDCl3) δ 7.81-7.84 (m, 3H), 7.42-7.46 (m, 2H), 7.34-7.37
(m, 3H), 7.32 (bd, J ) 8 Hz, 1H), 5.76 (m, 1H), 4.57 (m, 1H), 3.83-3.95
(m, 2H), 3.81 (bd, J ) 16 Hz, 1H), 3.73 (bd, J ) 16 Hz, 1H), 3.35-3.43
(m, 2H), 2.78 (m, 1H), 2.19 (s, 3H), 2.09-2.18 (m, 3H); HRMS (ES) exact
mass calcd for C25H25N5OCl (M + H+) 446.1742, found 446.1746. cis-13:
1H NMR (400 MHz, CDCl3) δ 7.88 (bs, 1H), 7.83 (d, J ) 8.3 Hz, 2H),
7.42-7.47 (m, 2H), 7.35 (m, 1H), 7.30 (m, 1H), 7.26 (d, J ) 8.3 Hz, 2H),
5.89 (dd, J ) 5.7 and 2.7 Hz, 1H), 4.54 (m, 1H), 3.82-3.92 (m, 2H), 3.78
(d, J ) 16.1 Hz, 1H), 3.65 (d, J ) 16.1 Hz, 1H), 3.36 (m, 1H), 3.22 (m,
1H), 2.55 (m, 1H), 2.46 (m, 1H), 2.33 (s, 3H), 2.09 (m, 1H), 1.75 (m, 1H);
HRMS (ES) exact mass calcd for C25H25N5OCl (M + H+) 446.1742, found
446.1732.
In summary, the cyclocondensation method described
herein for the synthesis of amino-substituted 5,6,7,8-tetrahy-
(14) The FTase inhibitory activity and dog pharmacokinetic (PK)
properties of 1 and the corresponding 2-methylimidazole analogue of 1 are
very similar, suggesting that the methyl groups in trans-13 and cis-13
contribute little to their inhibitory and PK activities (Merck Research
Laboratories, unpublished results).
(15) (a) Molecular modeling results, with relative energies in kcal/mol
shown in parentheses: trans-13 diequatorial half-chair (0.00); trans-13
diaxial half-chair (1.56); cis-13 equatorial-(ArCN)-axial-(piperazinone)
half-chair (0.18); cis-13 axial-(ArCN)-equatorial-(piperazinone) half-chair
(0.59); cis-13 diaxial boat (5.46). Conformations were generated using the
metric matrix distance geometry algorithm JG (S. Kearsley, Merck Research
Laboratories, unpublished). The structures were subjected to energy-
minimization within Macromodel (ref 15b) using the MMFF force field.
(b) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Caufield,
C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11,
440-467.
(12) Hoffman, R. W. Angew. Chem., Int. Ed. Engl. 1992, 31, 1124 and
references therein.
(13) For assay conditions, see: Graham, S. L.; deSolms, S. J.; Kohl, N.
E.; Mosser, S. D.; Oliff, A. I.; Pompliano, D. L.; Rands, E.; Breslin, M. J.;
Deanna, A. A.; Garsky, V. M.; Scholz, T. H.; Gibbs, J. B.; Smith, R. L. J.
Med. Chem. 1994, 37, 725-737.
(16) For the protocol for PK analysis, see: Olah, T. V.; McLoughlin,
D. A.; Gilbert, J. D. Rapid Commun. Mass Spectrom. 1997, 11, 17-23.
(17) Consistent with this hypothesis, metabolic clearance in dogs after
an intravenous dose was significantly reduced for trans-2 (1 mpk: CL )
1.40 mL/min/kg, t1/2 10.3 h) relative to 1 (2 mpk: CL ) 10.6 mL/min/kg).
Org. Lett., Vol. 2, No. 22, 2000
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