Several structurally unrelated scaffolds of the Rho kinase inhibitor were designed using pharmacophore information obtained from the results of a high-throughput screening and structural information from a homology model of Rho kinase. A docking simulation using the ligand-binding pocket of the Rho kinase model helped to comprehensively understand and to predict the structure-activity relationship of the inhibitors. This understanding was useful for developing new Rho kinase inhibitors of higher potency and selectivity. We identified several potent platforms for developing the Rho kinase inhibitors, namely, pyridine, 1H-indazole, isoquinoline, and phthalimide.
Treatment of N-(2- or 3-alkynyl)amino
esters with a low-valent titanium reagent
diisopropoxy(η2-propene)titanium (1), generated in situ by the reaction of
Ti(O-i-Pr)4 and 2i-PrMgCl,
resulted in an intramolecular nucleophilic
acyl substitution (INAS) reaction to afford
α-alkylidene-pyrrolidinones or -piperidinones. Thus, treatment
of
N-propargyl-anthranilates 5,
-indole-2-carboxylates 10, or -pyrrole-2-carboxylates
13 with 1 gave 4-quinolones
7,
[1,2-a]indoles, or [1,2-a]pyrroles,
respectively. Similarly, N-alkynylated α- or β-amino esters
14 or 15 with 1 afforded
N-heterocycles 18 or 19. In the reaction of
N-(2- or 3-alkenyl)amino esters with 1, the
resulting INAS product
underwent intramolecular carbonyl addition (ICA) reaction to afford the
N-heterocyclic compounds having a
cyclopropanol moiety in good to excellent yields. Thus, the
treatment of N-alkenyl-anthranilate 4a,
-indole-2-carboxylates 8 and 9, or -pyrrole-2-carboxylates
11 and 12 with 1 gave the
corresponding quinoline derivative 6a,
[1,2-a]indoles, or [1,2-a]pyrroles,
respectively. The optically active N-heterocyclic compounds
20 and 21 were
obtained from N-alkenylated α- or β-amino esters 16 or
17. A highly efficient total synthesis of
allopumiliotoxin
alkaloid 267A has also been accomplished. Thus, the
N-propargyl-2[(1-hydroxy-1-methoxycarbonyl)ethyl]pyrrolidine
24 (from l-proline in six steps) reacted with
1 to afford the corresponding indolidinone 25 in
67% yield, which has
previously been converted to allopumiliotoxin 267A.
The structure-activity relationship of Rho kinase inhibitors bearing an isoquinoline scaffold was studied. N-(1-Benzyl-3-pyrrolidyl)-N-(5-isoquinolyl)amine analogues were optimized with respect to their inhibitory potencies for the enzyme and for chemotaxis. The potent analogues were further evaluated by an ex vivo test in which the selected compounds were orally administered to rats, and the Rho kinase inhibitory potency observed in the rat serum was evaluated 3h after the administration. Compound 23g showed a high level of Rho kinase inhibitory activity in the rat serum and was stable in an in vitro metabolic test using a microsomal cytochrome preparation. The (R)-isomer of 23g displayed a higher level of inhibitory potency than the (S)-isomer in a cell-free kinase assay and in the cell migration assay (IC(50)(ENZ)=25 nM and IC(50)(MCP)=1 microM). The (R)-isomer successfully inhibited the phosphorylation of MBS (myosin-binding subunit) in cells.
Treatment of 1,1,3,3-tetrakis(alkylthio)-2-silapropanes with t-BuLi in THF at -40 °C generated 1,1,3,3-tetrakis(alkylthio)-1,3-dilithio-2-silapropanes which reacted with various bifunctional chlorosilanes to give the corresponding 4-to 7-membered polysilacycloalkanes in moderate to good yields. Furthermore, double alkylation of the dilithiated silanes with bis(halomethyl)diorganosilanes or dihaloalkanes was found to proceed smoothly giving rise to 1,4-disilacyclohexanes or silacycloalkanes in good yields, respectively, in THF and an aprotic polar co-solvent such as hexamethylphosphoric triamide (HMPA) or 1,1,3,3-tetramethylurea (TMU). The sulfenyl groups in the cyclized products were smoothly removed by radical reduction with tributyltin hydride.
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