Defining the active site of cytochrome P-450: the crystal and molecular structure of an inhibitor, SKF-525A

Abstract

The crystal and molecular structure of the cytochrome P-450 inhibitor, SKF-525A [2-(diethylamino)ethyl 2,2-diphenylpentenoate; proadifen hydrochloride] is described. Proadifen hydrochloride crystallized from an ethyl acetate and acetic acid mixture in the space group P2(1)/c with one molecule in the asymmetric unit. Cell constants are a = 18.716(4), b = 8.906(1), c = 14.201(3), beta = 109.41(1) degrees. The structure was solved using direct methods and was refined to an R value of 0.047; weighted R of 0.061 using 3757 reflections. From the crystal and molecular structure, it is seen that SKF-525A has two principal modes of complementary interactions with the enzyme available: polar and non-polar. Polar interactions that principally involve the chloride anion, the quaternary nitrogen atom and the carbonyl oxygen atom. In particular, there are two strong hydrogen bonds, one between Cl ... H-N, 3.090(1) A, the other between O2 ... H-C111 (one of the ethyl hydrogen atoms) at 3.411(2) A. The other is through non-polar interactions involving the phenyl and alkyl groups. Comparisons between proadifen hydrochloride and other inhibitors whose atomic coordinates are available reveal common features which correlate with their function. These include groups to provide necessary intermolecular contacts and bulk, such as a phenyl group and a hydrogen bond acceptor, as well as a tetrahedral atom, which allows for substrate flexibility.

An In-vitro Study on the Metabolism of Rokitamycin and Possible Interactions of the Drug with Rat Liver Microsomes

“…The effects of co-incubation of inhibitors speci®c for cytochrome P450 or esterases in the microsomal metabolism of rokitamycin were studied separately. Two so-called non-speci®c inhibitors of cytochrome P-450 in man, cimetidine (Somogyi & Muirhead 1987) and SKF-525A (Rossi et al 1987), were used to test possible inhibition of the formation of leucomycin A7 from rokitamycin in three different rat liver microsomes. The esterase inhibitors used were bis-nitrophenylphosphate, physostigmine and metrifonate (Hallak & Giacobini 1987;Iatsimirskaia et al 1997).…”

“…97%) inhibition. However, a so-called non-speci®c inhibitor of cytochrome P-450 isoforms in man, SKF-525A (Rossi et al 1987), also (by approx. 70%) inhibited the formation of leucomycin A7 (results not shown).…”

Συνθεση Νεων Αντιφλεγμονωδων Ενωσεων Με Βασικο Χαρακτηρα: Συσχετιση Δομικων Χαρακτηριστικων Και Δρασης Επι Ελευθερων Ριζων Μεταβολισμου Φαρμακων Και Φλεγμονης

“…Εδώ πρέπει να πούμε ότι και η αμινοπυρίνη είναι υπόστρωμα του κυτοχρώματος Ρ-450 και ειδικά του Ρ-4501Ι [137]. Είναι γνωστό ότι πολλοί αναστολείς του κυτοχρώματος Ρ-450 είναι επίσης και υποστρώματα αυτού και είναι συνηθισμένο φαινόμενο ενώσεις οι οποίες αλληλεπιδρούν με τα ένζυμα που μεταβολίζουν φάρμακα και δρουν σαν αναστολείς του κυτοχρώματος Ρ-450, να μπορούν επίσης να επάγουν αυτά τα ένζυμα [139]. Για παράδειγμα, είναι γνωστό ότι η προαδιφαίνη (SKF525-A) δρα σαν ισχυρός αναστολέας των μικροσωμικών μεταβολικών ενζύμων όταν χορηγείται μία φορά ενώ δρα σαν επαγωγέας όταν χορηγείται επανηλειμμένα [140].…”