ABSTRACT
A variety of C17 amide-substituted 6-azaandrost-4-en-3-ones were prepared and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Two series of potent and selective C17 amides were discovered, 2,5-disubstituted anilides and (arylcycloalkyl)amides. Compounds from each series with picomolar IC50's versus human type 2 5AR and low nanomolar to picomolar IC50's versus human type 1 5AR possessing 100-500-fold selectivity versus 3BHSD were identified. A conformational model to predict 3BHSD potency was developed which could rationalize 3BHSD potency within three different series of compounds. Evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor induced prostate involution, and pharmacokinetic measurements identified compounds (9, 12, 16, and 29) with good in vivo efficacy and half-life in the dog. An intact rat model of in vivo selectivity for 5AR versus 3BHSD inhibition was also developed. Dual inhibitors of both human 5AR's may show advantages over type 2 selective 5AR inhibitors, such as finasteride (1), in the treatment of disease states which depend upon dihydrotestosterone.
Subject(s)
3-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , 5-alpha Reductase Inhibitors , Adrenal Glands/enzymology , Azasteroids/pharmacology , Steroid Isomerases/antagonists & inhibitors , Animals , Azasteroids/chemistry , Azasteroids/pharmacokinetics , Dogs , Humans , Male , Models, Molecular , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
6-Azaandrost-4-en-3-ones were synthesized and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) to explore the structure-activity relationship of this novel series in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Compounds with picomolar IC50's versus human type 2 5AR and low nanomolar Ki's versus human type 1 5AR with 100-fold selectivity versus 3BHSD were identified (70). Preliminary in vivo evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor-induced prostate involution and dog pharmacokinetic measurements identified a series of 17 beta-[N-(diphenylmethyl)carbamoyl]-6-azaandrost-4-en-3-ones (compounds 54, 66, and 67) with good in vivo efficacy and half-life in the dog. Inhibitors with, at the minimum, low nanomolar potency toward both human 5AR's and selectivity versus 3BHSD may show advantages over previously known 5AR inhibitors in the treatment of disease states which depend upon dihydrotestosterone, such as benign prostatic hyperplasia.
Subject(s)
3-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , 5-alpha Reductase Inhibitors , Adrenal Glands/enzymology , Azasteroids/pharmacology , Isoenzymes/antagonists & inhibitors , Steroid Isomerases/antagonists & inhibitors , Animals , Azasteroids/chemistry , Dogs , Humans , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipSubject(s)
5-alpha Reductase Inhibitors , Azasteroids/chemical synthesis , Isoenzymes/antagonists & inhibitors , Animals , Azasteroids/pharmacology , Baculoviridae/genetics , Cell Line , Dihydrotestosterone/metabolism , Humans , Male , Moths , Orchiectomy , Rats , Rats, Sprague-Dawley , Recombinant Proteins/antagonists & inhibitors , Testosterone/metabolism , TransfectionABSTRACT
A series of 11 8-substituted xanthines having three different substitution patterns on the 1- and 3-positions [pattern a (R1 = R3 = CH2CH2CH3), b (R1 = CH2CH2CH3, R3 = CH3), and c (R1 = CH3, R3 = CH2CH2CH3)] was prepared. These compounds were assessed for affinity and selectivity in binding to adenosine A1 and A2 receptors. Compounds with greatest affinity at the A1 receptor had the 1,3-substitution pattern a. With one exception, compounds with pattern a also exhibited the most potent binding at the A2 receptor; however, several compounds with pattern c were equipotent at the A2 receptor with those having pattern a. Additionally, the substituents on the 1- and 3-positions of these 8-substituted xanthines were equally important for determining maximum affinity to the A1 receptor, while the substituent at the 3-position is more important than the substituent at the 1-position for potency at the A2 receptor. As a result of this, it is possible to maximize selectivity for the A1 receptor by choice of the 1- and 3-position substituents. However, the R1/R3 substitution pattern required for maximum A1 selectivity is also dependent upon the substituent in the 8-position in a manner which is not fully understood.
