Biomolecular chemistry of isopropyl fibrates

Abstract

Isopropyl 2-[4-(4-chlorobenzoyl)-phenoxy]-2-methylpropanoic acid and isopropyl 2-(4-chlorophenoxy)-2-methylpropanoate, also known as fenofibrate and isopropyl (iPr) clofibrate, are hypolipidemic agents of the fibrate family. In a previously reported triclinic structure of fenofibrate (polymorph I), the methyl groups of the iPr moiety are located symmetrically about the carboxylate group. We report a new monoclinic form (polymorph II) of fenofibrate and a first structural description of iPr clofibrate, and in these the methyl groups are placed asymmetrically about the carboxylate group. In particular, the dihedral (torsion) angle between the hydrogen atom on the secondary C and the C atom of the carboxyl group makes a 2.74° angle about the ester O···C bond in the symmetric fenofibrate structure of polymorph I, whereas the same dihedral angle is 45.94° in polymorph II and -30.9° in the crystal structure of iPr clofibrate. Gas-phase density functional theory (DFT) geometry minimizations of fenofibrate and iPr clofibrate result in lowest energy conformations for both molecules with a value of about ±30° for this same angle between the OC-O-C plane and the C-H bond of the iPr group. A survey of crystal structures containing an iPr ester group reveals that the asymmetric conformation is predominant. Although the hydrogen atom on the secondary C atom of the iPr group is located at a comparable distance from the carbonyl oxygen in the symmetric and asymmetric fenofibrate (2.52 and 2.28 Å) and the iPr clofibrate (2.36 Å) structures, this hydrogen atom participates in a puckered five-membered ring arrangement in the latter two that is unlike the planar arrangement found in symmetric fenofibrate (polymorph I). Polar molecular surface area values indicate fenofibrate and iPr clofibrate are less able to act as acceptors of hydrogen bonds than their corresponding acid derivatives. Surface area calculations show that dynamic polar molecular surface area values of the iPr esters of the fibrates are lower than those of their acids, implying that the fibrates have better membrane permeability and a higher absorbability and hence are better prodrugs when these agents need to be orally administered.

Figure 1

Chemical structures of (I) fenofibric acid, (2-[4-(4-chlorobenzoyl)-phenoxy]-2-methylpropanoic acid); (II) fenofibrate, (isopropyl 2-[4-(4-chlorobenzoyl)-phenoxy]-2-methylpropanoic acid ); (III) clofibric acid, (2-(4-chlorophenoxy)-2-methylpropionic acid); and (IV) isopropyl clofibrate, (isopropyl 2-(4-chlorophenoxy)-2-methylpropanoate).

Figure 2

Crystal structures of fibrates in the Thermal Ellipsoid Plot representation. Atom labels and numbering shown are same as what was deposited in the CSD and used in the text. 2a. Isopropyl clofibrate (50% probability thermal ellipsoids),. Isopropyl group is asymmetric about the ester bond. 2b. Redetermined crystal structure of Clofibric acid. 2c. Redetermined crystal structure of fenofibrate in the symmetric polymorph I. Isopropyl group is symmetric about the ester bond in the triclinic crystal form. 2d. Crystal structure of fenofibrate in the new asymmetric polymorph II. Isopropyl group is asymmetric about the ester bond in the monoclinic crystal form.

Figure 3

Schematic drawing of the chemical structure of fenofibrate. Atom numbering shown is based on the asymmetric crystal polymorph II of fenofibrate and as employed in the crystal structures that are indicated in the relevant OTEP diagrams above (Figure 2). To avoid crowding only selected atoms numbers are shown here. Arrows indicate the rotation about bonds corresponding to the torsion angles ι₁, ι₂ and ι₃.

Figure 4

Overlay of fibrates. 4a. Left and 4b. right correspond to superimposition of dimethyl and phenyl ring groups, respectively of isopropyl clofibrate (magenta), fenofibrate (yellow), fenofibric acid (purple), redetermined clofibric acid (white) and fenofibrate II (tan). Only non-hydrogen atoms are shown. C atoms are colored as indicated in parentheses based on the compound. To provide better contrast from the color of the C skeleton O atoms are kept in red and Cl in green or pink.

Figure 5

Superimposition of fenofibrate polymorphs and fenofibric acid. Crystal structure of the symmetric form of fenofibrate (TADLIU), asymmetric form of fenofibrate and fenofibric acid (QANHUJ) were overlaid in yellow, green and orange color, respectively. Hydrogen and oxygen atoms are shown in white and red while chlorine is marked in green (fenofibrate polymorph II and fenofibric acid) and purple (fenofibrate polymorph I).

Figure 6

π-stacking and dimer formation in the triclinic form of fenofibrate. The calculated interaction energy for the shown pair of molecules is -38.7 kJ/mol, the interplanar separation between the two chlorobenzene rings is 3.486 Å.

Figure 7

Energy profile and related conformation. a. Relaxed PES scan of the isopropyl ester of clofibrate at the B3LYP/6-31G(d) level with minima and conformers labeled. b. Only selected conformations about the ester bond rotation with molecular structures, carbon (grey), hydrogen (white), oxygen (red), and chlorine (green) are shown. The carbonyl oxygen O(3) is omitted for clarity. The angle measured is the dihedral angle of H(28)-C(15)-O(4)-C(14). Conformations with the H atom of the isopropyl group with larger torsion angles have lower energy than those with smaller angles.

Figure 8

Polar Histogram plot of the isopropyl ester torsion angle, (ι₁) C-O-C-H, based on a CSD database search (CSD V5.32, updates until May 2011). Total of 212 compounds were included in the study after removal of 8 double entries. For compounds in which the isopropyl group is disordered only the major conformer was retained. The total number of isopropyl ester groups considered was 348 in the survey.

Figure 9

Change of surface area (Ų) relative to the ester bond torsion angle ι₁ in iPr fibrate derivatives. Total ASA and MSA for fenofibrate and iPr clofibrate are broken down into their polar and nonpolar components.