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At least 307 records · Page 17Linked to original sources
PubMed2003

Safety and tolerability of the dual 5alpha-reductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia.

OBJECTIVE: The objective of this paper is to examine safety and tolerability data from a number of recently completed clinical trials with the novel, dual 5alpha-reductase inhibitor, dutasteride. METHODS: Intent-to-treat analyses were conducted on data for dutasteride 0.5 mg/day for drug-related adverse events, clinical laboratory test results, and prostate-specific antigen (PSA) levels derived from four large, randomised, double-blind clinical trials (n=5655). Further data were derived from a randomised, double-blind combination study of dutasteride 0.5 mg/day and tamsulosin 0.4 mg/day (n=327), and several safety studies conducted in healthy volunteers. RESULTS: Data from two-year blinded clinical studies demonstrate that dutasteride is well tolerated, with a profile comparable with that of placebo. The exception is a modestly elevated incidence of impotence, decreased libido, ejaculation disorders, and gynaecomastia. Clinical laboratory test abnormalities were reported by <1% of patients treated with dutasteride, and abnormal values occurred with similar frequency versus placebo-treated patients. In a healthy volunteer study, when dutasteride was administered daily for 1 year, it did not significantly affect bone metabolism markers, bone mineral density or lipid profiles. Dutasteride reduced total serum PSA concentrations by approximately 50% following 6, 12, and 24 months of treatment but had no effect on free-to-total PSA levels. The safety profile of dutasteride did not differ from that of finasteride in a large, parallel-group, comparator trial. Additionally, when dutasteride was used in combination with an alpha(1)-blocker, the drug-related adverse event profiles were as would be expected for the individual agents. CONCLUSIONS: Considered together, these data demonstrate dutasteride to be well-tolerated.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2003

Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride.

OBJECTIVES: The Symptom Management After Reducing Therapy (SMART-1) study examined the combination of the dual action 5alpha-reductase inhibitor (5ARI) dutasteride, and alpha(1)-blocker tamsulosin, followed by withdrawal of tamsulosin in men with symptomatic BPH. METHODS: 327 BPH patients were randomised to 0.5mg dutasteride and 0.4 mg tamsulosin for 36 weeks (DT36) or 0.5 mg dutasteride and 0.4 mg tamsulosin for 24 weeks followed by dutasteride and tamsulosin matched placebo for the remaining 12 weeks (DT24+D12). Patients' assessment of their symptoms, IPSS at weeks 24, 30, and drug safety were evaluated. RESULTS: 77% of DT24+D12 patients felt the same/better at week 30 compared with week 24 (changes in IPSS were consistent with this finding). Of those subjects with an IPSS <20 who changed to dutasteride monotherapy at week 24, 84% switched without a noticeable deterioration in their symptoms. In the 27% of men with severe baseline symptoms (IPSS >or=20) who had withdrawal of tamsulosin therapy at week 24, 42.5% reported a worsening of their symptoms compared with 14% in the DT36 group. The regimens were well tolerated. CONCLUSIONS: Dutasteride can be used in a 24-week combination with tamsulosin, to achieve rapid onset of symptom relief in patients at risk of underlying disease progression. This symptom relief is maintained in the majority of patients after the alpha(1)-blocker is removed from the combination. Patients with severe symptoms may benefit from longer-term combination therapy.

Adrenergic alpha-Antagonists↗
PubMed1998

Determination of a novel selective inhibitor of type 1 5alpha-reductase in human plasma by liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry.

A sensitive and specific assay of human plasma for the determination of (5alpha,7beta,16beta)-16[(4-chlorophenyl)oxy]-4,7- dimethyl-4-aza-androstan-3-one (I), a selective inhibitor of human type 1 5alpha-reductase, has been developed. The method is based on high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS-MS) detection. The analyte (I) and internal standard, Proscar (II), were isolated from the basified biological matrix using a liquid-liquid extraction with methyl-tert.-butyl ether (MTBE). The organic extract was evaporated to dryness, the residue was reconstituted in mobile phase and injected into the HPLC system. The MS-MS detection was performed on a PE Sciex API III Plus tandem mass spectrometer using a heated nebulizer interface. Multiple reaction monitoring using the precursor-->product ion combinations of m/z 430-->114 and 373-->305 was used to quantify I and internal standard (II), respectively. The assay was validated in the concentration range of 0.5 to 500 ng/ml in human plasma. The precision of the assay, expressed as coefficient of variation (C.V.), was less than 7% over the entire concentration range, with adequate assay specificity and accuracy. The HPLC-MS-MS method provided sufficient sensitivity to completely map the 24 h pharmacokinetic time-course following a single 0.5 mg dose of I.

Azasteroids↗
PubMed2003

Solid phase transition of CS-891 enantiotropes during grinding.

The physical properties of N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17beta-carboxamide (CS-891), a novel and orally effective testosterone 5-reductase inhibitor, were investigated by differential scanning calorimetry, powder X-ray diffraction at elevated temperature and single crystal X-ray crystallography. CS-891 was revealed to exist as two enantiotropic forms, a low-temperature stable form (Form A) and a high-temperature stable form (Form B) which reversibly transforms to Form A at around 58 degrees C. The effect of grinding temperature on the transition of CS-891 between the amorphous and the crystalline state during grinding of the eantiotropes was examined. Form A transformed into an amorphous form during the grinding process while the product temperature was kept below the transition temperature. On the other hand, when the product temperature during grinding reached above the transition temperature, Form A transformed into an amorphous form and some of the amorphous form converted back to Form B. Form B crystallized from the amorphous form was physically stable even at below the transition temperature. The amorphous form in equilibrium with Form B exhibited remarkable physical stability in comparison with the amorphous form obtained by continued grinding below the transition temperature.

5-alpha Reductase Inhibitors↗
PubMed1999

Validation of a population pharmacokinetic/pharmacodynamic model for 5 alpha-reductase inhibitors.

A population pharmacokinetic/dynamic model describing the conversion of testosterone to dihydrotestosterone (DHT) by 5alpha-reductases and the irreversible inhibition of 5alpha-reductase(s) by finasteride and dutasteride was validated. The model had been developed using data from a single dose study in healthy volunteers and was validated against data from a 28-day repeat dose study in patients with benign prostatic hyperplasia. Validation was carried out by comparing results of Monte Carlo simulations to the observed data, fitting the model to the repeat dose data and comparing with previously derived parameter values, and examining individual predictions of the model for the individuals in the repeat dose study for any bias. Simulations closely predicted the outcome of the repeat dose study, estimated parameters of the pharmacodynamic modelling were generally close to within 88 to 116% of those from the original model and the individual predictions did not indicate any bias. Thus the model derived from single dose data from healthy volunteers was considered to be valid for the prediction of DHT levels in the patient population after repeated dosing of dutasteride and finasteride.

5-alpha Reductase Inhibitors↗
PubMed1996

Characterization of 5alpha-reductase gene expression in stroma and epithelium of human prostate.

The expression of 5alpha-reductase type 1 and type 2 isoenzymes in hyperplastic human prostate tissue and several human prostate cell lines was investigated by Northern blot analyses, reverse transcription-polymerase chain reaction (RT-PCR), and enzyme activity. Separation of stroma and epithelium was confirmed histologically and only preparations with no apparent contamination were employed in the subsequent studies. Poly(A)+ RNA was isolated from stromal and epithelial fractions and analysed by Northern blot and RT-PCR. Inhibition of epithelial and stromal 5alpha-reductase activities by 17beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5alpha-androstan- 3-one (4MA) was assessed using a range of concentrations between 10(-13) and 10(-5) M. Results from Northern blot analyses and RT-PCR showed that the prostate stroma expressed 5alpha-reductase type 1 and type 2 isoenzymes, whereas the prostate epithelium only expressed 5alpha-reductase type 1. This was consistent with biphasic inhibition of 5alpha-reductase activity by 4MA in stroma and monophasic inhibition in epithelium. Cultured epithelial cells derived from human prostate only expressed 5alpha-reductase type 1 and had Vmax and Km values that approximated the lower end of the range reported for surgically removed prostate epithelium. The foregoing data explains the disparate activities of 5alpha-reductase, previously reported, in stroma and epithelium. The differential localization of these isoenzymes in the prostate suggests that future therapy of androgen-sensitive disease may be more successful through the use of selective inhibitors of the different 5alpha-reductase isoenzymes.

Aged↗
PubMed1997

4-Methyl-3-oxo-4-aza-5alpha-androst-1-ene-17beta-N-aryl-carboxamides: an approach to combined androgen blockade [5alpha-reductase inhibition with androgen receptor binding in vitro].

4-Aza-5alpha-androstan-3-one 17beta-(N-substituted carboxamides) are potent human type 2 5alpha-reductase (5aR) inhibitors with generally poor binding to the human androgen receptor (hAR). When the 17-amide N-substituent included an aromatic residue, potent dual inhibitors of both type 1 and 2 5aR are produced, but hAR binding remained poor. Tertiary-substituted-17-amides have reduced inhibition of both 5aR isozymes. The addition of an N4-methyl substitutent to the A-ring profoundly increased hAR affinity and the addition of unsaturation to the A-ring (delta1) modestly augmented hAR binding. The unsubstituted carbanilides in the delta1-N4-methyl series show some selectivity for type 1 5aR over the type 2 isozyme, whereas addition of aryl substituents, particularly at the 2-position, increased type 2 5aR binding to provide dual inhibitors with excellent hAR binding, e.g. N-(2-chlorophenyl)-3-oxo-4-methyl-4-aza-5alpha-androst-1-ene-17bet a-carboxamide (9c). Compounds of this type exhibit low nanomolar IC50s for both human 5aR isozymes as well as the human androgen receptor. Kinetic analysis confirms that the prototype 9c displays reversible, competitive inhibition of both human isozymes of 5aR with K(i) values of less than 10 nM. Furthermore, this compound binds to the androgen receptor with an IC50 equal to 8 nM. Compounds in this series are projected to be powerful antagonists of testosterone and dihydrotestosterone action in vivo, with potential utility in the treatment of prostatic carcinoma (PC).

5-alpha Reductase Inhibitors↗
PubMed1998

Mechanism based representation of the active site of 5 alpha-reductase (5AR).

In the present study, we have attempted to determine a detailed representation of the 5 alpha-Reductase (5AR) active site involving the elucidation of the transition state for the steroid delta 4 reduction reaction (the 'NADPH-substrate' complex), onto which steroidal and non-steroidal inhibitors were superimposed. We conclude that: (i) there is a requirement for groups to mimic the steroid substrate A-ring; (ii) the area about C(3), C(4), C(5) and C(6) of T appears to be sterically hindered, and; (iii) the area of the active site about the C(17) of the steroid substrate does not possess hydrogen bonding groups and is not restricted.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2001

Structure-activity relationship of aza-steroids as PI-PLC inhibitors.

A number of aza-steroids were synthesized as potent phosphatidylinositol phospholipase C (PI-PLC) inhibitors. The epimeric mixtures 22,25-diazacholesterol (8a) and 3beta-hydroxy-22,25-diazacholestane (8b) were among the most active of these inhibitors, with IC(50) values of 7.4 and 7.5 microM, respectively. The 20alpha epimer, 8a2 (IC(50)=0.64 microM), whose stereochemistry at C-20 coincides with that of cholesterol, was found 50 times more potent than the 20beta epimer, 8a1 (IC(50)=32.2 microM). In diaza-estrone derivatives, the 3-methoxy group on the aromatic A-ring of 23 exhibited moderate PI-PLC inhibitory activity (IC(50)=19.7 microM), while compound with a free hydroxyl group (21) was inactive. However, in diaza-pregnane derivatives, epimers with a 3-hydroxyl group (8a, IC(50)=7.4 microM) exhibited more potent PI-PLC inhibitory activity than their counterparts with 3-methoxyl group on the non-aromatic A-ring (26, IC(50)=17.4 microM). We have illustrated in our previous publication that 3-hydroxyl-6-aza steroids are potent PI-PLC inhibitors.(3) However, simultaneous presence of the 6-aza and 22,25-diaza moieties in one molecule as in 13, led to loss of activity. Epimeric mixture 8a showed selective growth inhibition effects in the NCI in vitro tumor cell screen with a mean GI(50) value (MG-MID) of 5.75 microM for 54 tumors.

Azacosterol↗
PubMed1993

Finasteride: a slow-binding 5 alpha-reductase inhibitor.

A microsomal preparation of human prostatic tissue was used to study the kinetics of interaction of steroid 5 alpha-reductase with finasteride, a known 5 alpha-reductase inhibitor. This molecule has been reported to reversibly bind 5 alpha-reductase in a competitive manner to testosterone with a Ki value in the 10 nM range. The results presented in this paper show that enzyme-inhibitor complex formation does not take place instantaneously as assumed in previous studies. At neutral pH and 37 degrees C, the association of enzyme with inhibitor is governed by a rate constant, kon, of 2.7 x 10(5) M-1 s-1. This low kon value, in combination with the high energy of activation of the association reaction (150 kJ mol-1), indicates that the association process is not diffusion controlled and may proceed through intermediate steps. However, such an intermediate was not detected kinetically under the inhibitor concentrations investigated. We therefore conclude that the equilibrium dissociation constant, Ki*, for the initial binding of the enzyme to the inhibitor is higher than 1.5 x 10(7) M. Even at inhibitor concentrations as low as 1 nM, the reaction was completely displaced to the EI complex and no residual activity detected once the equilibrium was reached. Hence, the interaction between finasteride and 5 alpha-reductase can also be characterized by a very low overall equilibrium dissociation constant (Ki << 10(-9) M), at least 1 order of magnitude lower than previously reported values.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1991

Evidence for distinct dehydrogenase and isomerase sites within a single 3 beta-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase protein.

Complementary DNA encoding human 3 beta-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase (3 beta-HSD) has been expressed in transfected GH4C1 with use of the cytomegalovirus promoter. The activity of the expressed protein clearly shows that both dehydrogenase and isomerase enzymatic activities are present within a single protein. However, such findings do not indicate whether the two activities reside within one or two closely related catalytic sites. With use of [3H]-5-androstenedione, the intermediate compound in dehydroepiandrosterone (DHEA) transformation into 4-androstenedione by 3 beta-HSD, the present study shows that 4MA (N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide) and its analogues inhibit DHEA oxidation competitively while they exert a noncompetitive inhibition of the isomerization of 5-androstenedione to 4-androstenedione with an approximately 1000-fold higher Ki value. The present results thus strongly suggest that dehydrogenase and isomerase activities are present at separate sites on the 3 beta-HSD protein. In addition, using 5 alpha-dihydrotestosterone (DHT) and 5 alpha-androstane-3 beta, 17 beta-diol as substrates for dehydrogenase activity only, we have found that dehydrogenase activity is reversibly and competitively inhibited by 4MA. Such data suggest that the irreversible step in the transformation of DHEA to 4-androstenedione is due to a separate site possessing isomerase activity that converts the 5-ene-3-keto to a much more stable 4-ene-3-keto configuration.

Androgen Antagonists↗
PubMed1989

3 Beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase from bovine adrenals: mechanism of inhibition by 3-oxo-4-aza steroids and kinetic mechanism of the dehydrogenase.

Several 3-oxo-4-aza steroids (1) have been identified as inhibitors of the 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase catalyzed conversion of pregnenolone to progesterone. By kinetically decoupling the two enzyme activities isolated from bovine adrenal cortex, it has been demonstrated that inhibition by 1 occurs through interference of both activities. A preferred ordered association of substrates to the 3 beta-hydroxy-delta 5-steroid dehydrogenase in which the cofactor binds prior to steroid was determined by isotope exchange at equilibrium. With this result, the dead-end inhibition patterns of 1 with the dehydrogenase were interpreted to originate from a preferred association of inhibitor within an enzyme ternate containing NADH; this proposal is supported by data from multiple inhibition analysis indicating synergistic binding of NADH and 1. Similarly, inhibition of the 3-keto-delta 5-steroid isomerase by the 3-oxo-4-aza steroids was enhanced in the presence of the positive effector NADH. On the basis of pH profiles upon Vm, Vm/Km, and 1/Ki for both enzyme activities, inhibition is proposed to result from the structural similarity of 1 to intermediate states formed upon enzyme catalysis.

3-Hydroxysteroid Dehydrogenases↗
PubMed1996

Inhibition of human steroid 5alpha reductases type I and II by 6-aza-steroids: structural determinants of one-step vs two-step mechanism.

We have discovered that 17beta-[N,N-(diethyl)carbamoyl]-6-azaandrost-4-en-3-one is a time-dependent inhibitor of type II 5alpha-reductase, as is the drug finasteride. Unlike finasteride, the 6-aza-steroid is not a time-dependent inhibitor of type I 5 alpha-reductase. Finasteride inhibition of type II enzyme proceeds in a two-step mechanism. At pH 6 and 37 degrees C, an initial finasteride-reductase complex is formed with a K(i)(app) of 11.9 +/- 4.1 nM. In a second step, an irreversible complex is formed with a rate constant of inactivation of 0.09 +/- 0.01 s(-1). In contrast, the 6-aza-steroid is a reversible inhibitor. From the results of a simplified mathematical analysis, based on the rapid equilibrium approximation, the inhibitor and the enzyme form an initial complex with a K(i) of 6.8 +/- 0.2 nM. The reversible formation of a final complex, with an overall K(i) of 0.07 +/- 0.02 nM, is characterized by a first-order isomerization rate constant 0.0035 +/- 0.0001 s(-1) for the forward step and 0.00025 +/- 0.00006 s(-1) for the backward step. All rate constants for the two-step mechanism were obtained by using a general numerical integration method. The best fit values for the association and dissociation rate constants were 5.0 microM(-1) s(-1) and 0.033 +/- 0.008 s(-1), respectively, and the isomerization rate constants were 0.0035 +/- 0.007 s(-1) and 0.000076 +/- 0.000019 s(-1). These values correspond to an initial K(i) of 6.5 nM and an overall dissociation constant of 0.14 nM. The data presented here show that both finasteride and the 6-aza-steroid analogs are potent against type II 5alpha-reductase, although their mechanisms of inhibition are different.

5-alpha Reductase Inhibitors↗
PubMed1996

Sterol biosynthesis: strong inhibition of maize delta 5,7-sterol delta 7-reductase by novel 6-aza-B-homosteroids and other analogs of a presumptive carbocationic intermediate of the reduction reaction.

A series of mono- and diazasteroids have been synthesized as analogs of a predicted carbocationic intermediate of delta 5,7-sterol delta 7-reductase (delta 7-SR). 6-Aza-B-homo-5 alpha-cholest-7-en-3 beta-ol (4), a novel compound whose synthesis is described for the first time, and 6,7-diaza-5 alpha-cholest-8(14)-en-3 beta-ol (6) were shown to be very powerful inhibitors of delta 7-SR in a preparation isolated from maize (Zea mays) (K(i),app = 50-70 nM, Ki,app/Km,app = 1.0 x 10(-4) to 1.3 x 10(-4). The data are consistent with a carbonium ion mechanism for the reduction; compounds 4 and 6 probably act as reaction intermediate analogs. Compound 4, in contrast to compound 6, displayed in the same microsomal preparation more than 50-fold selectivity for inhibition of the delta 7-SR versus delta 8-delta 7-sterol isomerase, cycloeucalenol isomerase, and delta 8,14-sterol delta 14-reductase, the mechanism of these four enzymes involving presumptive cationic intermediates centered respectively at C7, C8, C9, and C14. These observations highlight the paramount importance of the location of the positively charged nitrogen atom(s) in the B-ring structure for selectivity among these enzymes involving structurally close cationic reaction intermediates. Efficient in vivo inhibition of sterol biosynthesis in bramble cell suspension cultures by a low concentration of compound 4 was demonstrated and confirmed the in vitro properties of this derivative.)

Azasteroids↗
PubMedDate not supplied

Engineering lipobeads: properties of the hydrogel core and the lipid bilayer shell.

We previously reported on a novel system termed Lipobead that consists of hydrogel beads encased within an anchored lipid bilayer. The hydrogel particles are formed by inverse suspension polymerization of dimethylacrylamide with N,N'-ethylenebis(acrylamide). During the polymerization stage, the water in oil emulsion is interfacially stabilized by small molecule surfactants as well as a small percentage of lipid functionalized with a vinyl group. The functionalized lipid becomes tethered to the bead surface and promotes the assembly of a lipid bilayer on the surface of the hydrogel beads. The presence of the functionalized lipid during polymerization dramatically alters the yield, average size, and size distribution of beads produced. This paper examines the effect of various chemical and physical processing parameters on the average size and size distribution of beads produced when lipid is a component of the surfactant mixture. Relationships between the processing parameters, average bead size, and size distribution were established. Macroscopic properties of the lipid bilayers of Lipobeads were also evaluated including phase transition temperature as well as permeability to the small polar molecule, adenosine triphosphate. It was established that the presence of functionalized lipid improves the organization of the bilayer on the Lipobead surface.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1995

Structure-activity relationships for inhibition of type 1 and 2 human 5 alpha-reductase and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase by 6-azaandrost-4-en-3-ones: optimization of the C17 substituent.

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.

3-Hydroxysteroid Dehydrogenases↗
PubMed1992

Structure and molecular modeling of GABAA receptor antagonists.

The recently described potent and selective GABAA antagonist SR 95531 (gabazine) is compared to six other GABAA antagonists: (+)-bicuculline, (-)-securinine, (+)-tubocurarine, iso-THAZ, R-5135, and pitrazepine. Starting from ab initio molecular orbital calculations performed on crystal atomic coordinates, attempts were made to identify in each structure the functional groups that are involved in receptor recognition and binding. A molecular modeling study revealed that (a) all compounds possess accessible cationic and anionic sites separated by an 4.6-5.2 A intercharge distance, (b) the antagonistic nature of the compounds can be explained by the presence of additional binding sites, (c) the correct spatial orientation of the additional binding sites is crucial for GABAA selectivity, and (d) the criteria determining the potency of the antagonist effect are an accurate intercharge distance (greater than 5 A) and the existence of hydrogen-bonding functionalities on one of the additional ring system. The presented pharmacophore accounts also for the inactivity of closely related compounds such as (-)-bicuculline, adlumidine, virosecurinine, allosecurinine, and the 4,6-diphenyl analogue of gabazine.

Alkaloids↗