title: Structure-activity relationship study of human liver microsomes-catalyzed hydrolysis rate of ester prodrugs of MENT by comparative molecular field analysis (CoMFA).
abstract: A series of MENT esters (3-71) was designed, prepared and tested to study the structure-activity relationship (SAR) of the hydrolysis rate with human liver microsomes of these prodrugs. Compounds were obtained covering a wide range of metabolic stability. The results are useful for the proper selection of prodrugs for different pharmaceutical formulations to deliver the potent and prostate-sparing androgen MENT. The MENT esters can especially be administered for male hormone replacement therapy and male contraception. Comparative molecular field analysis (CoMFA) was applied to a dataset of 28 esters, for which ED50 values could be obtained. The CoMFA model where the electrostatic and H-bond molecular fields were combined turned out to be most predictive. Despite the limited size of the dataset, CoMFA can help to rationalize the SAR of the ester hydrolysis rate of ester prodrugs of MENT.
authors.affiliation: N.V. Organon, Research & Development Laboratories, Molenstraat 110, PO Box 20, 5340 BH, Oss, The Netherlands.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bursi
authors.forename: Arijan
authors.initials: A
authors.lastname: Grootenhuis
authors.forename: Jaap
authors.initials: J
authors.lastname: van der Louw
authors.forename: Jos
authors.initials: J
authors.lastname: Verhagen
authors.forename: Marcel
authors.initials: M
authors.lastname: de Gooyer
authors.forename: Peter
authors.initials: P
authors.lastname: Jacobs
authors.forename: Dirk
authors.initials: D
authors.lastname: Leysen
mesh_terms: D004952:Esters / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008958:Models, Molecular; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D004952:Esters; C064709:trestolone; D009277:Nandrolone