Mark A. Levy

Inhibitors of steroid 5α-Reductase in benign prostatic hyperplasia, male pattern baldness and acne

Benign prostatic hyperplasia is an androgen-dependent disease which afflicts a large percentage of males over the age of fifty, and is usually treated by surgery. Dihydrotestosterone, a 5 alpha-reduced metabolite of testosterone, has been implicated as a causative factor in the progression of the disease, largely through the clinical study of males who are genetically deficient in the dihydrotestosterone-producing enzyme, steroid 5 alpha-reductase. As a result, inhibition of this enzyme has become a pharmacological strategy for the treatment of benign prostatic hyperplasia as well as other dihydrotestosterone-related disorders such as acne and male pattern baldness. In this review, Brian Metcalf and colleagues focus on the chemical and kinetic mechanisms of steroid 5 alpha-reductase, and known inhibitors of this enzyme, and discuss the rationale behind the design of a mechanistically distinct class of steroid 5 alpha-reductase inhibitors.

Preparative chiral HPLC separation of all possible stereoisomers of LY191704 and LY266111 and their in vitro inhibition of human types 1 and 2 steroid 5α-reductases

Abstract A preparative chiral HPLC separation of each of the four stereoisomers of LY191704 [(±)-1, and (±)-3] and LY266111 [(±)-2, and (±)-4] is reported. All eight compounds have been evaluated in vitro as inhibitors of recombinant human type 1 and type 2 steroid 5α-reductase. The trans enantiomers of LY266111, (+)-2 and (−)-2, show equal and potent inhibition of the type 1 isozyme. The cis enantiomers of LY266111, (+)-4 and (−)-4, and the unsaturated analogue 6 show significantly reduced type 1 inhibitory activity. The cis and trans enantiomeric pairs of LY191704 [(+)-1, (−)-1, (+)-3, and (−)-3] and the unsaturated analog 5 display similar and potent activity against the type 1 isozyme. All compounds display relatively poor activity against the human type 2 isozyme.

Interaction between rat prostatic steroid 5α-reductase and 3-Carboxy-17β-substituted steroids: Novel mechanism of enzyme inhibition☆

Efforts to identify novel compounds capable of blocking the steroid 5α-reductase (SR) catalyzed conversion of testosterone (T) to 5α-dihydrotestosterone have resulted in the development of 17β-substituted-3-androstene-3-carboxylic acids as potent inhibitors of the rat prostatic enzyme. The dead-end inhibition patterns of one of these steroidal acrylates, 17β-N-(2-methyl-2-propyl)-carbamoyl-androst-3,5-diene-3-carboxylic acid were best evaluated with a linear uncompetitive kinetic model vs both T (K ii =11±1 nM) and NADPH (K ii =22±2 nM)

A non-steroidal diene acid inhibitor of human type 2 stereoid 5α-reductase

Abstract A series of 4a-methyl-3,4,4,4a-9-tetrahydrophenanthrene-2-carboxylic acids and 2-phosphinic acids has been prepared and evaluated in vitro as inhibitors of human recombinant steroid 5α-reductase. 7-Chloro-4a-methyl-3,4,4,4a-9-tetrahydrophenanthrene-2-carboxylic acid 5, is a marginally selective inhibitor of human type 2 steroid 5α-reductase (Ki,app = 260 nM). The phosphinic acid compounds, 8 and 9, are weak inhibitors of types 1 and 2 steroid 5α-reductase.

The synthesis of novel bridged A ring steroids

Abstract The novel bridged A ring steroid 1 was synthesized as a potential inhibitor of steroid 5α-reductase. The structure of the key synthetic intermediate, pentacyclic enedione 2 was confirmed by x-ray analysis.

A comparison of steroidal and non-steroidal inhibitors of human steroid 5α-reductase: New tricyclic aryl acid inhibitors of the type-1 isozyme

Abstract A series of 9,10-dihydrophenanthrene-2-carboxylic acids has been prepared and evaluated in vitro as inhibitors of human recombinant steroid 5α-reductase. 7-Bromo-9,10-dihydrophenanthrene-2-carboxylic acid, 8c, is a potent and selective non-steroidal inhibitor of human type-1 steroid 5α-reductase (Ki,app 26 nM). The inhibitory activity relationships of steroidal and non-steroidal inhibitors, with 4-aza, 6-aza, diene acid, aryl acid and nitro-alkenes functionalities, are considered.

Inhibition and time-dependent inactivation of human placental aromatase by 3-oxo-17β-carboxamido steroids

Several N,N-dialkyl-3-oxo-4-aza-17 beta-carboxamido steroids were found to be competitive inhibitors versus androstenedione (AND) and time-dependent inactivators of aromatase activity from human term placental microsomes. Inhibition constants (Kis) from dead-end inhibition analyses indicated interactions between these compounds and the enzyme over a 0.8-7 microM inhibitor concentration range. The affinity of these compounds for aromatase leading to the time-dependent loss of enzyme activity was several fold higher than that estimated by the steady-state kinetics, with rate constants of inactivation of 0.025-0.033 min-1. 3-Oxo-4-aza steroids lacking a 17 beta-carboxamide were found to be competitive inhibitors of AND for aromatase, but did not inactivate enzyme activity in a time-dependent manner. Steroids which did not contain a 4-aza substituent, but retained the 17 beta-carbamoyl functionality, were both inhibitors and inactivators of aromatase activity in the microsomes. The time-dependent loss of aromatase activity induced by these compounds was shown to require reducing equivalents as provided by NADPH. Hence, it is suggested that the inactivation of aromatase by compounds in this series is dependent on enzymatic activation in the presence of the N,N-dialkyl-17 beta-carbamoyl substituent.

Inhibition of pyridine-nucleotide-dependent enzymes by pyrazoles. Synthesis and enzymology of a novel a-ring pyrazole steroid

A novel A-ring pyrazole steroid, 2,3-bisaza-A-nor-1,5(10)-estradien-17 beta-ol (3), was synthesized as a potential inhibitor of steroidal NAD(P)H-dependent oxidoreductases. Compound 3 proved to be a potent inhibitor of 3(17)beta-hydroxysteroid dehydrogenase (from P. testosteroni) exhibiting a Ki of 90 +/- 20 nM. The activities of 3 alpha,20 beta-hydroxysteroid dehydrogenase (from S. hydrogenans), steroid-5 alpha-reductase (from rat prostate), and 3 alpha-hydroxysteroid dehydrogenase (from rat liver) were unaffected by pyrazole 3. Dead end inhibition studies indicate an ordered binding of cofactor prior to substrate or pyrazole inhibitor.

The preparation and evaluation of (+/-)-trans-1-Diazo-8-methoxy-4a-methyl-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-2-one as an inhibitor of human type-1 steroid 5α-reductase

Abstract (+/-)- trans -1-Diazo-8-methoxy-4a-methyl-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-2-one has been prepared and evaluated in vitro as an inhibitor of type-1 (K i,app 120 nM) and type-2 (K i,app 2000 nM) human recombinant steroid 5α-reductases.

Preparation and biological activity of tricyclic non-steroidal inhibitors of human steroid 5α-reductase

The synthesis and in vitro inhibitory studies against human types 1 and 2 steroid 5α-reductase of a series of 9,10-dihydrophenanthrene-2-carboxylic acids is reported. A (4-carboxy)phenyl substituent at C-7 provides a compound with activity against both isozymes. The structural features responsible for activity are discussed.