sildenafil and Erectile-Dysfunction

Novel pyrimidine-5-carboxamide derivatives bearing a 3-chloro-4-methoxybenzylamino group at the 4-position were identified as potent and highly selective phosphodiesterase 5 inhibitors. Among them, we successfully found 10j (avanafil) which exhibited a potent relaxant effect on isolated rabbit cavernosum (EC30=2.1 nM) and a high isozyme selectivity.

Topics: Animals; Erectile Dysfunction; Humans; Male; Phosphodiesterase 5 Inhibitors; Pyrimidines; Rabbits

In a continuing effort to discover novel PDE5 inhibitors, we have successfully found quinazolines with 4-benzylamino substitution as potent and selective PDE5 inhibitors. Initial lead compound (1) was found to be easily metabolized when incubated with human liver microsomes mainly through C6 amide hydrolysis. Blocking of this metabolic hot spot led to discovery of 10 (CKD533) which is highly potent, selective and orally efficacious in conscious rabbit model for erectile dysfunction and now is undergoing preclinical toxicology study.

Topics: Administration, Oral; Animals; Carbamates; Catalytic Domain; Computer Simulation; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Enzyme Inhibitors; Erectile Dysfunction; Humans; Male; Microsomes, Liver; Phosphodiesterase 5 Inhibitors; Quinazolines; Rabbits; Rats

In our efforts to minimize the side effects associated with low selectivity against the other PDE isozymes, a novel class of 2-phenylquinazolin-4(3H)-one derivatives were designed and prepared as potent PDE5 inhibitors with high selectivity against PDE6. The syntheses and SAR studies of such molecules were reported.

Topics: Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Cyclic Nucleotide Phosphodiesterases, Type 6; Erectile Dysfunction; Male; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Quinazolinones; Rats; Structure-Activity Relationship

The 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one, sildenafil, is a cGMP-specific phosphodiesterase-5 (PDE5) inhibitor used for penile erectile dysfunction. In the search for more potent and selective PDE5 inhibitors, new sildenafil analogues (6a-v), characterized by the presence on the sulfonyl group in the 5' position of novel N-4-substituted piperazines or ethylenediamine moiety, were prepared by traditional and microwave-assisted synthesis and tested in rabbit isolated aorta and corpus cavernosum. Similarly to sildenafil, several analogues showed IC50 values in the nanomolar range. In the in vitro studies, all the tested compounds caused concentration-dependent relaxations in both rabbit isolated aorta and corpus cavernosum. All sildenafil analogues potentiated the nitric oxide-dependent vasodilation in endothelium-intact rabbit aorta. Compound 6f exhibited great pEC50 value in corpus cavernosum, and compounds 6r and 6u in isolated aorta were found as potent as sildenafil for inhibiting PDE5. Because several analogues were significantly more lipophilic than sildenafil, these compounds may offer a new lead for development of new sildenafil analogues.

Topics: Animals; Aorta; Blood Platelets; Endothelium, Vascular; Erectile Dysfunction; Humans; In Vitro Techniques; Magnetic Resonance Spectroscopy; Male; Muscle Relaxation; Muscle, Smooth; Penis; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Pyrimidines; Rabbits; Rats; Sildenafil Citrate; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship; Sulfones

Plant extracts traditionally used for male impotence (Tribulus terrestris, Ferula hermonis, Epimedium brevicornum, Cinnamomum cassia), and the individual compounds cinnamaldehyde, ferutinin, and icariin, were screened against phosphodiesterase-5A1 (PDE5A1) activity. Human recombinant PDE5A1 was used as the enzyme source. Only E. brevicornum extract (80% inhibition at 50 microg/mL) and its active principle icariin (1) (IC50 5.9 microM) were active. To improve its inhibitory activity, 1 was subjected to various structural modifications. Thus, 3,7-bis(2-hydroxyethyl)icaritin (5), where both sugars in 1 were replaced with hydroxyethyl residues, potently inhibited PDE5A1 with an IC50 very close to that of sildenafil (IC50 75 vs 74 nM). Thus, 5 was 80 times more potent than 1, and its selectivity versus phosphodiesterase-6 (PDE6) and cyclic adenosine monophosphate-phosphodiesterase (cAMP-PDE) was much higher in comparison with sildenafil. The improved pharmacodynamic profile and lack of cytotoxicity on human fibroblasts make compound 5 a promising candidate for further development.

Topics: Cyclic Nucleotide Phosphodiesterases, Type 6; Epimedium; Erectile Dysfunction; Ferula; Flavonoids; Humans; Inhibitory Concentration 50; Male; Molecular Structure; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Plant Extracts; Purines; Sildenafil Citrate; Structure-Activity Relationship; Sulfones; Tribulus

A series of potent chiral PDE5 inhibitors are described that are based on the sildenafil architecture but exhibit much greater selectivity over PDE6. Eudismic analysis of the SAR in this series provided a clear illustration of Pfeiffer's rule and indicated that the chiral motif was involved in a highly-stereoselective interaction with PDE5. This PDE5 specificity translated to levels of selectivity over PDE6 that were hitherto unprecedented in the sildenafil scaffold. UK-371,800 (compound 8) was identified as a development candidate from this series that married sildenafil-like molecular properties with high selectivity over PDE6. Clinical data confirm that UK-371,800 has markedly superior human pharmacokinetics to a previously-described higher molecular weight achiral analogue in this template (compound 1).

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Combinatorial Chemistry Techniques; Cyclic Nucleotide Phosphodiesterases, Type 6; Dose-Response Relationship, Drug; Erectile Dysfunction; Humans; Male; Molecular Structure; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Structure-Activity Relationship; Sulfones

In an effort to minimize side effects associated with low selectivity against PDE isozymes, we have successfully identified a series of 6,7,8-substituted quinzaolines as potent inhibitors of PDE5 with high level of isozyme selectivity, especially against PDE6 and PDE11. PDE5 potency and isozyme selectivity of quinazolines were greatly improved with substitutions both at 6- and 8-position. The synthesis, structure-activity relationships and in vivo efficacy of this novel series of potent PDE5 inhibitors are described.

Topics: Combinatorial Chemistry Techniques; Erectile Dysfunction; Humans; Male; Molecular Structure; Penile Erection; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Quinazolines; Structure-Activity Relationship

Sildenafil (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C(max) of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2) was selected for progression into the clinic.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Animals; Azetidines; Biological Availability; Caco-2 Cells; Crystallography, X-Ray; Cyclic Nucleotide Phosphodiesterases, Type 5; Dogs; Dose-Response Relationship, Drug; Erectile Dysfunction; Humans; Ketones; Male; Models, Molecular; Molecular Structure; Pyrimidines; Pyrimidinones; Structure-Activity Relationship

Pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones and their analogues, potentially useful for the treatment of erectile dysfunction, were synthesized and evaluated as inhibitors of phosphodiesterase 5 (PDE5). Several compounds showed IC50 values in the low nanomolar range, and in particular, compound 5r, displaying high potency toward PDE5 (IC50 = 8.3 nM) and high selectivity versus PDE6 (240-fold) appeared to be a very promising new lead both in comparison with the potent but not selective sildenafil and in comparison with some analogues previously reported by us. SAR studies in this triheterocyclic scaffold led us to conclude that the best arranged groups are a methyl in position 1, a benzyl in position 3, a phenyl in position 9, and a linear four-carbon chain in position 6.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cattle; Cyclic Nucleotide Phosphodiesterases, Type 5; Enzyme Inhibitors; Erectile Dysfunction; Humans; Isoenzymes; Male; Molecular Structure; Phosphoric Diester Hydrolases; Pyrazoles; Pyridazines; Stereoisomerism; Structure-Activity Relationship; Substrate Specificity

We previously reported a series of potent and selective pyrimidinyl pyrroloquinolone PDE5 inhibitors such as 2a for potential use in male erectile dysfunction (MED) (Sui, Z.; Guan, J.; Macielag, M. J.; Jiang, W.; Zhang, S.; Qiu, Y.; Kraft, P., Bhattacharjee, S.; John, T. M.; Craig, E.; Haynes-Johnson, D.; Clancy, J. J. Med. Chem. 2002, 45, 4094-4096). Unfortunately, the low aqueous solubility and poor oral bioavailability rendered them undesirable development candidates. To address this issue, we designed a series of analogues using two approaches: increasing the overall basicity and reducing molecular weight of the lead. Through earlier SAR studies, we discovered that the PDE5 potency of the pyrroloquinolones is insensitive to substitution on the pyrrole nitrogen. Basic functional groups such as pyridines and benzimidazoles were appended via the aromatic ring connected to the pyrrole nitrogen. Several truncated analogues were also designed and synthesized to improve oral absorption. These modifications allowed us to identify analogues with good oral bioavailability in rats, dogs, and monkeys while the high potency against PDE5 and desirable selectivity versus other PDE isozymes were maintained. Compounds R-11e and R-11l were selected as development candidates for MED and other indications.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Biological Availability; Blood Pressure; Cell Line; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Dogs; Electric Stimulation; Erectile Dysfunction; Macaca mulatta; Male; Penis; Pyrroles; Quinolones; Rats; Rats, Sprague-Dawley; Solubility; Stereoisomerism; Structure-Activity Relationship

In search of a PDE5 inhibitor for erectile dysfunction, an SAR was developed from a PDE1/PDE5 purine series of leads, which had modest PDE5 potency and poor isozyme selectivity. A compound (41) with PDE5 inhibition and in vivo activity similar to sildenafil was discovered from this effort. In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Humans; Male; Models, Molecular; Molecular Structure; Phosphodiesterase I; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Rats; Sildenafil Citrate; Structure-Activity Relationship; Sulfones; Vasodilator Agents

Development of structure-activity relationship of cyclic guanines I lead us to discovery of a potent and selective series of phosphodiesterase 5 inhibitors 52-59 (IC50=1.3-11.0 nM, PDE6/5=116-600).

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Delivery Systems; Erectile Dysfunction; Guanine; Humans; Male; Phosphodiesterase Inhibitors; Polycyclic Compounds; Structure-Activity Relationship

In a continuing effort to discover novel chemotypes as potent and selective PDE5 inhibitors for the treatment of male erectile dysfunction (ED), we have found that 4-benzylaminoquinoline derivatives are very potent and selective PDE5 inhibitors. Some compounds in this series had PDE5 IC(50)'s as low as 50 pM. While an electron withdrawing group at the C6-position of the quinoline substantially improved PDE5 potency, an ethyl group at the C8-position not only improved the PDE5 potency but also the isozyme selectivity. Substitutents at the C3-position can incorporate a variety of different groups. The synthesis and primary structure-activity relationship of this new series of potent PDE5 inhibitors are described.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Humans; Male; Phosphodiesterase Inhibitors; Quinolines

Synthesis of furoyl and benzofuroyl pyrroloquinolones as potent and selective PDE5 inhibitors was reported. Their in vitro potencies in inhibiting PDE5 and selectivity in inhibiting other PDE isozymes (PDE1-4 and PDE6) were evaluated. Some of these compounds are more potent than sildenafil with better selectivity toward PDE1 and PDE6. Incorporation of solublizing groups resulted in bioavailable analogues. Selected compounds showed in vivo efficacy in anesthetized dog model for penile erection.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Biological Availability; Cell Line; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Dogs; Erectile Dysfunction; Furans; Isoenzymes; Male; Penile Erection; Quinolones; Rats; Structure-Activity Relationship

Novel pyrazolopyridopyridazine derivatives have been prepared as potent and selective PDE5 inhibitors. Compound 6 has been identified as a more potent and selective PDE5 inhibitor than sildenafil (1). It is as efficacious as sildenafil in in vitro and in vivo PDE5 inhibition models, and it is orally bioavailable in rats and dogs. The superior isozyme selectivity of 6 is expected to exert less adverse effects in humans when used for erectile dysfunction treatment.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Animals; Biological Availability; Blood Pressure; Cyclic Nucleotide Phosphodiesterases, Type 5; Dogs; Enzyme Inhibitors; Erectile Dysfunction; Female; Male; Penis; Pyridazines; Rabbits; Rats; Structure-Activity Relationship

A series of N(2)-furoyl and N(2)pyrimidinyl beta-carbolines was discovered to possess potent inhibitory activity against PDE5. During the synthesis we developed a tandem resin quenching protocol, which allowed us to synthesize large number of target compounds in a rapid fashion. Representative compounds exhibit superior selectivity to sildenafil versus other isozymes of PDEs, and demonstrated in vivo efficacy in increasing introcavernosal pressure in dogs.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Blood Pressure; Carbolines; Combinatorial Chemistry Techniques; Cyclic Nucleotide Phosphodiesterases, Type 5; Dogs; Drug Evaluation, Preclinical; Erectile Dysfunction; Humans; Isoenzymes; Male; Penis; Piperazines; Purines; Sildenafil Citrate; Solubility; Structure-Activity Relationship; Sulfones

2-aryl-substituted imidazo[5,1-f][1,2,4]triazin-4(3H)-ones represent a new class of potent cGMP-PDE 5 inhibitors that prove to be superior to other purine-isosteric inhibitors. Subnanomolar inhibitors of PDE 5 with activity in in vivo models for erectile dysfunction have been identified. BAY 38-9456 (Vardenafil-hydrochloride) has been selected for clinical studies in the indication of erectile dysfunction.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Enzyme Inhibitors; Erectile Dysfunction; Imidazoles; Inhibitory Concentration 50; Male; Protein Binding; Rabbits; Structure-Activity Relationship; Triazines

A series of N-pyrimidinylpyrroloquinolones were discovered as extremely potent and selective PDE5 inhibitors. Representative compounds demonstrated in vivo efficacy in dog erectile dysfunction models and are orally bioavailable.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Animals; Biological Availability; Cyclic Nucleotide Phosphodiesterases, Type 5; Dogs; Enzyme Inhibitors; Erectile Dysfunction; Male; Quinolones; Rats; Structure-Activity Relationship

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Dogs; Erectile Dysfunction; In Vitro Techniques; Male; Muscle Relaxation; Muscle, Smooth; Penis; Phosphodiesterase Inhibitors; Pyridines; Rabbits; Rats; Structure-Activity Relationship

Phosphodiesterase type 5 (PDE5) inhibitors with improved PDE isozyme selectivity relative to sildenafil may result in agents for the treatment of male erectile dysfunction (MED) with a lower incidence of PDE-associated adverse effects. This paper describes the discovery of 14, a PDE5 inhibitor with improved potency and selectivity in vitro compared to sildenafil. This compound shows activity in a functional assay of erectile function comparable to that of sildenafil.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Imidazoles; In Vitro Techniques; Male; Penis; Phosphodiesterase Inhibitors; Piperazines; Purines; Purinones; Quinazolines; Rabbits; Sildenafil Citrate; Structure-Activity Relationship; Sulfones