ABSTRACT
BACKGROUND: Cryosurgery is the most commonly used method to treat actinic keratosis (AK). Cryosurgical methods are not standardized. OBJECTIVE: To examine differences in the spray techniques used for liquid nitrogen cryosurgery when treating AKs of the head, and the effect of these variations in technique on rates of complete clearance of AKs. MATERIALS AND METHODS: Patients were those from the FIELD-1 study, who received cryosurgery as per the investigators' usual practice to all AKs. This was followed by topical treatment with either vehicle gel or ingenol mebutate gel, 0.015%, after 3 weeks. The investigator recorded the average duration of cryosurgery spray used, the number of freeze-thaw cycles, and the distance from the tip of the spray device to the AK. Clearance rates were determined at Week 11. RESULTS: Less-aggressive freezing techniques were used for AKs on the face than for those on the scalp. However, higher rates of complete clearance on the face and scalp were associated with more-aggressive freezing techniques. CONCLUSION: Patients with AKs on the face receive less-aggressive cryosurgery than do patients with AKs on the scalp.
Subject(s)
Cryosurgery , Dermatologic Agents/administration & dosage , Diterpenes/administration & dosage , Keratosis, Actinic/drug therapy , Keratosis, Actinic/surgery , Administration, Cutaneous , Adolescent , Adult , Cryosurgery/adverse effects , Cryosurgery/methods , Face/surgery , Gels/administration & dosage , Humans , Keratosis, Actinic/pathology , Risk Factors , Scalp/surgery , Severity of Illness Index , Treatment Outcome , United StatesABSTRACT
We report the discovery of piperazine urea based compound 1, a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist. Compound 1 shows anti-obesity efficacy without potentiating erectile activity in the rodent models.
Subject(s)
Piperazines/chemistry , Receptor, Melanocortin, Type 4/agonists , Urea/analogs & derivatives , Administration, Oral , Animals , Biological Availability , Disease Models, Animal , Dogs , Drug Evaluation, Preclinical , Eating/drug effects , Haplorhini , Mice , Obesity/drug therapy , Piperazines/pharmacokinetics , Piperazines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/genetics , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity Relationship , Urea/chemistry , Urea/pharmacokinetics , Urea/therapeutic useABSTRACT
We report an SAR study of MC4R analogs containing spiroindane heterocyclic privileged structures. Compound 26 with N-Me-1,2,4-triazole moiety possesses exceptional potency at MC4R and potent anti-obesity efficacy in a mouse model. However, the efficacy is not completely mediated through MC4R. Additional SAR studies led to the discovery of compound 32, which is more potent at MC4R. Compound 32 demonstrates MC4R mediated anti-obesity efficacy in rodent models.
Subject(s)
Obesity/drug therapy , Receptor, Melanocortin, Type 4/agonists , Triazoles/pharmacology , Animals , Chromatography, High Pressure Liquid , Disease Models, Animal , Mice , Mice, Knockout , Molecular Structure , Rats , Receptor, Melanocortin, Type 4/genetics , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/therapeutic useABSTRACT
Design, syntheses and structure-activity relationships of N-acetylated piperazine privileged structures containing MC4R agonist compounds were described. The most potent derivatives were low nM MC4R selective full agonists. Several compounds from the series had modest pharmacokinetic properties.
Subject(s)
Ligands , Receptor, Melanocortin, Type 4/agonists , Animals , Humans , Piperazine , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity RelationshipABSTRACT
We report a series of potent and selective MC4R agonists based on spiroindane amide privileged structures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid synthesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese (DIO) rat models.
Subject(s)
Amides/chemistry , Anti-Obesity Agents/chemistry , Obesity/drug therapy , Pyrrolidines/chemistry , Receptor, Melanocortin, Type 4/agonists , Spiro Compounds/chemistry , Amides/pharmacokinetics , Amides/therapeutic use , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/therapeutic use , Body Weight/drug effects , Humans , Mice , Mice, Knockout , Pyrrolidines/pharmacokinetics , Pyrrolidines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/metabolism , Spiro Compounds/pharmacokinetics , Spiro Compounds/therapeutic use , Structure-Activity RelationshipABSTRACT
Design, synthesis, and SAR of a series of 3H-spiro[isobenzofuran-1,4'-piperidine] based compounds as potent, selective and orally bioavailable melanocortin subtype-4 receptor (MC4R) agonists are disclosed.
Subject(s)
Piperidines/chemistry , Receptor, Melanocortin, Type 4/agonists , Administration, Oral , Animals , Brain/metabolism , Crystallography, X-Ray , Drug Evaluation, Preclinical , Humans , Molecular Conformation , Piperidines/chemical synthesis , Piperidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/metabolism , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
Selective estrogen receptor modulators (SERMs) interact with estrogen receptors as agonists or antagonists depending on the target tissue. Currently available SERMs are used to treat and prevent breast cancer and osteoporosis, to treat ovulatory dysfunction in women, and for contraception. Because current therapies do not adequately treat menopausal symptoms, the search continues for the optimal SERM for postmenopausal women, which would relieve hot flushes, treat vaginal atrophy, and prevent fractures, while protecting the endometrium, breast, and cardiovascular system. Future use of SERMs may also include their use in a tissue selective estrogen complex (TSEC), a therapy that combines a SERM with estrogen(s), designed to deliver the efficacy of each component with improved overall tolerability for the treatment of postmenopausal women. The future of SERMs may also include their use in men for the treatment of osteoporosis and various syndromes associated with secondary hypogonadism and possibly prostate cancer. Continued research should allow the full potential of SERMs to be uncovered.
Subject(s)
Postmenopause , Selective Estrogen Receptor Modulators/therapeutic use , Breast Neoplasms/drug therapy , Clinical Trials as Topic , Female , Humans , Osteoporosis, Postmenopausal/drug therapyABSTRACT
We report the design, synthesis and properties of spiroindane based compound 1, a potent, selective, orally bioavailable, non-peptide melanocortin subtype-4 receptor agonist. Compound 1 shows excellent erectogenic activity in the rodent models.
Subject(s)
Erectile Dysfunction/drug therapy , Indans/chemistry , Indans/therapeutic use , Receptor, Melanocortin, Type 4/agonists , Receptor, Melanocortin, Type 4/metabolism , Spiro Compounds/chemistry , Spiro Compounds/therapeutic use , Animals , CHO Cells , Cricetinae , Cricetulus , Dogs , Haplorhini , Humans , Indans/pharmacokinetics , Indans/pharmacology , Male , Mice , Molecular Structure , Protein Binding , Rats , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Structure-Activity RelationshipSubject(s)
Peptides/pharmacology , Receptors, Melanocortin/agonists , Amino Acid Sequence , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Peptides/chemistryABSTRACT
Discovery of a series of tert-butyl pyrrolidine derived, potent and orally bioavailable melanocortin receptor subtype-4 (MC4R) selective modulators is disclosed.
Subject(s)
Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Receptor, Melanocortin, Type 4/agonists , Administration, Oral , Humans , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , TelomeraseABSTRACT
Alpha-melanotropin (alphaMSH), Ac-Ser1-Tyr2-Ser3-Met4-Glu5-His6-Phe7-Arg8-Trp9-Gly10-Lys11-Pro12-Val13-NH2,(1) has been long recognized as an important physiological regulator of skin and hair pigmentation in mammals. Binding of this peptide to the melanocortin receptor 1 (MC1R) leads to activation of tyrosinase, the key enzyme of the melanin biosynthesis pathway. In this study, interactions of the human MC1bR (an isoform of the receptor 1a) with the synthetic cyclic analogs of alphaMSH were studied. These ligands were analogs of MTII, Ac-Nle4-cyclo-(Asp5-His6-D-Phe7-Arg8-Trp9-Lys10)-NH2, a potent pan-agonist at the human melanocortin receptors (hMC1,3-5R). In the structure of MTII, the His6-D-Phe7-Arg8-Trp9 segment has been recognized as "essential" for molecular recognition at the human melanocortin receptors (hMC1,3-5R). Herein, the role of the Trp9 in the ligand interactions with the hMC1b,3-5R has been reevaluated. Analogs with various amino acids in place of Trp9 were synthesized and tested in vitro in receptor affinity binding and cAMP functional assays at human melanocortin receptors 1b, 3, 4 and 5 (hMC1b,3-5R). Several of the new peptides were high potency agonists (partial) at hMC1bR (EC50 from 0.5 to 20 nM) and largely inactive at hMC3-5R. The bulky aromatic side chain in position 9, such as that in Trp, was found not to be essential to agonism (partial) of the studied peptides at hMC1bR.
Subject(s)
Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Receptor, Melanocortin, Type 1/agonists , alpha-MSH/analogs & derivatives , alpha-MSH/pharmacology , Binding, Competitive , Cyclic AMP/analysis , Cyclic AMP/biosynthesis , Humans , Inhibitory Concentration 50 , Molecular Structure , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/isolation & purification , Peptides, Cyclic/metabolism , Receptor, Melanocortin, Type 1/chemistry , Receptor, Melanocortin, Type 1/classification , Sensitivity and Specificity , Structure-Activity Relationship , alpha-MSH/chemical synthesis , alpha-MSH/chemistry , alpha-MSH/isolation & purification , alpha-MSH/metabolismABSTRACT
alpha-Melanocyte stimulating hormone (alphaMSH), Ac-Ser(1)-Tyr(2)-Ser(3)-Met(4)-Glu(5)-His(6)-Phe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH(2), is an endogenous agonist for the melanocortin receptor 1 (MC1R), the receptor found in the skin, several types of immune cells, and other peripheral sites. Three-dimensional models of complexes of this receptor with alphaMSH and its synthetic analog NDP-alphaMSH, Ac-Ser(1)-Tyr(2)-Ser(3)-Nle(4)-Glu(5)-His(6)-D-Phe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH(2), have been previously proposed. In those models, the 6-9 segment of the ligand was considered essential for the ligand-receptor interactions. In this study, we probed the role of Trp(9) of NDP-alphaMSH in interactions with hMC1bR. Analogs of NDP-alphaMSH with various amino acids in place of Trp(9) were synthesized and tested in vitro in receptor affinity binding and cAMP functional assays at human melanocortin receptors 1b, 3, 4, and 5 (hMC1b,3-5R). Several new compounds displayed high agonist potency at hMC1bR (EC(50) = 0.5-5 nM) and receptor subtype selectivity greater than 2000-fold versus hMC3-5R. The Trp(9) residue of NDP-alphaMSH was determined to be not essential for molecular recognition at hMC1bR.
Subject(s)
Receptor, Melanocortin, Type 1/agonists , Receptor, Melanocortin, Type 1/chemistry , Tryptophan/physiology , alpha-MSH/chemistry , alpha-MSH/pharmacology , Amino Acid Sequence , Amino Acid Substitution , Binding Sites , Binding, Competitive/drug effects , Humans , Ligands , Molecular Structure , Peptides/chemistry , Peptides/pharmacology , Receptor, Melanocortin, Type 1/classification , Structure-Activity Relationship , alpha-MSH/analogs & derivativesABSTRACT
SAR about the piperidine core in a series of MC4R agonists is described. A number of alkyl substituents that furnish compounds with good affinity and functional potency are reported.
Subject(s)
Alkanes/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Receptor, Melanocortin, Type 4/agonists , Receptor, Melanocortin, Type 4/metabolism , Alkanes/chemical synthesis , Alkanes/chemistry , Amides/chemistry , Humans , Molecular Structure , Nitriles/chemistry , Piperidines/chemical synthesis , Structure-Activity Relationship , Tetrazoles/chemistryABSTRACT
Melanocortin receptors (MC1-5R) and their endogenous ligands (melanocyte-stimulating hormones and adrenocorticotropic hormone) are involved in many physiological processes in humans. Of those receptors, the actions of MC5R are the least understood despite its broad presence in the numerous peripheral tissues and brain. In this study, we describe synthesis and pharmacological properties in vitro (receptor-binding affinity and agonist activity) of several cyclic analogs of alphaMSH which are potent agonists at hMC5R (EC(50) below 1 nM) and of enhanced receptor subtype selectivity (more than 2000-fold versus hMC1b,3R and about 70- to 200-fold versus hMC4R). These compounds are analogs of Ac-Nle(4)-cyclo[Asp(5)-His(6)-D-Nal(2')(7)-Pip(8)-Trp(9)-Lys(10)]-NH(2) (Pip: pipecolic acid) in which His(6) has been replaced with sterically hindered amino acids. They may be useful tools in the elucidation of the MC5R role in skin disorders and in immunomodulatory and in anti-inflammatory actions of alphaMSH.
Subject(s)
Receptors, Corticotropin/agonists , alpha-MSH/agonists , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Receptors, MelanocortinABSTRACT
The physiological role of melanocortin receptor 5 (MC5R) in humans is not clear despite its broad presence in various peripheral sites and in the brain, cortex, and cerebellum. To differentiate between functions of this receptor and those of the other melanocortin receptors (hMC1,3,4R), peptides with improved receptor subtype selectivity are needed. The endogenous ligands, melanocortins, and their various synthetic analogues are not particularly selective for hMC5R. In this study, cyclic peptides derived from MTII, Ac-Nle-cyclo(Asp-His6-D-Phe7-Arg8-Trp-Lys)-NH2 (a pan-agonist at the melanocortin receptors) were prepared and tested in binding and functional assays on CHO cells expressing hMC1b,3-5R. The analogues included in their structures sterically constrained hydrophobic amino acids in positions 6 (His) and 8 (Arg), and the D-4,4'-biphenyl residue in position 7 (D-Phe). Several of the new compounds were selective potent agonists at hMC5R. They are exemplified by peptide 29, Ac-Nle-cyclo(Asp-Oic6-D-4,4'-Bip7-Pip8-Trp-Lys)-NH2 (Oic=octahydroindole-2-COOH; 4,4'-Bip=4,4'-biphenylalanine; Pip=pipecolic acid) of IC50=0.95 nM and EC50=0.99 nM at hMC5R and selectivity for this receptor with respect to the other melanocortin receptors greater than 5000-fold.
Subject(s)
Peptides, Cyclic/chemical synthesis , Receptors, Corticotropin/agonists , alpha-MSH/analogs & derivatives , alpha-MSH/chemical synthesis , Animals , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Cyclic AMP/biosynthesis , Humans , Melanocyte-Stimulating Hormones/chemical synthesis , Melanocyte-Stimulating Hormones/chemistry , Melanocyte-Stimulating Hormones/pharmacology , Peptides, Cyclic/pharmacology , Radioligand Assay , Receptors, Melanocortin , Structure-Activity Relationship , alpha-MSH/pharmacologyABSTRACT
Alpha-melanotropin, Ac-Ser(1)-Tyr-Ser-Met-Glu-His(6)-Phe(7)-Arg(8)-Trp(9)-Gly-Lys-Pro-Val(13)-NH(2)(1), is a non-selective endogenous agonist for the melanocortin receptor 5; the receptor present in various peripheral tissues and in the brain, cortex and cerebellum. Most of the synthetic analogs of alphaMSH, including a broadly used and more potent the NDP-alphaMSH peptide, Ac-Ser(1)-Tyr-Ser-Nle(4)-Glu-His(6)-D-Phe(7)-Arg(8)-Trp(9)-Gly-Lys-Pro-Val(13)-NH(2), are also not particularly selective for MC5R. To elucidate physiological functions of the melanocortin receptor 5 in rodents and humans, the receptor subtype selective research tools are needed. We report herein syntheses and pharmacological evaluation in vitro of several analogs of NDP-alphaMSH which are highly potent and specific agonists for the human MC5R. The new linear peptides, of structures and solubility properties similar to those of the endogenous ligand alphaMSH, are exemplified by compound 7, Ac-Ser(1)-Tyr-Ser-Met-Glu-Oic(6)-D-4,4'-Bip(7)-Pip(8)-Trp(9)-Gly-Lys-Pro-Val(13)-NH(2) (Oic: octahydroindole-2-COOH, 4,4'-Bip: 4,4'-biphenylalanine, Pip: pipecolic acid), shortly NODBP-alphaMSH, which has an IC(50)=0.74 nM (binding assay) and EC(50)=0.41 (cAMP production assay) at hMC5R nM and greater than 3500-fold selectivity with respect to the melanocortin receptors 1b, 3 and 4. A shorter peptide derived from NODBP-alphaMSH: Ac-Nle-Glu-Oic(6)-D-4,4'-Bip(7)-Pip(8)-Trp(9) -NH(2) (17) was measured to be an agonist only 10-fold less potent at hMC5R than the full length parent peptide. In the structure of this smaller analog, the Nle-Glu-Oic(6)-D-4,4'-Bip(7)-Pip(8) segment was found to be critical for high agonist potency, while the C-terminal Trp(9) residue was shown to be required for high hMC5R selectivity versus hMC1b,3,4R.
Subject(s)
Receptors, Corticotropin/metabolism , alpha-MSH/metabolism , Amino Acid Sequence , Animals , CHO Cells , Cricetinae , Cricetulus , Cyclic AMP/metabolism , Humans , Molecular Structure , Protein Binding/drug effects , Receptors, Corticotropin/agonists , Receptors, Corticotropin/genetics , Receptors, Melanocortin , Structure-Activity Relationship , alpha-MSH/analogs & derivatives , alpha-MSH/pharmacologyABSTRACT
Design and synthesis of potent MC4 selective agonists based on cyclohexylpiperidine derived cyclic urea, oxazolidinones, and sulfonamide based privileged structures are disclosed.
Subject(s)
Drug Design , Receptor, Melanocortin, Type 4/agonists , Receptor, Melanocortin, Type 4/metabolism , Humans , Ligands , Molecular Structure , Sensitivity and Specificity , Structure-Activity Relationship , Substrate SpecificityABSTRACT
The melanocortin subtype-4 receptor (MC4R) has been implicated in the control of feeding behavior and body weight regulation. A series of tetrapeptides, based on Tic-DPhe-Arg-Trp-NH2-a mimic of the putative message sequence "His-Phe-Arg-Trp" and modified at the DPhe position, were prepared and pharmacologically characterized for potency and selectivity. Substitution of His with Tic gave peptides with significant increases in selectivity. The effects of the substitution pattern of DPhe were investigated and it has significant influences on potency and the level of the maximum cAMP accumulation. Intracerebroventricular administration of peptide 10 induced significant inhibition of cumulative overnight food intake and feeding duration in rats.
Subject(s)
Appetite Depressants/administration & dosage , Appetite Depressants/chemical synthesis , Eating/drug effects , Oligopeptides/administration & dosage , Oligopeptides/chemical synthesis , Receptor, Melanocortin, Type 4/metabolism , Animals , Appetite Depressants/metabolism , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Eating/physiology , Humans , Male , Models, Molecular , Oligopeptides/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Optimization of the biological activity of a new class of non-peptidyl, pyridazinone derived human melanocortin subtype-4 receptor agonists is disclosed.
Subject(s)
Drug Design , Pyridazines/chemistry , Pyridazines/pharmacology , Receptor, Melanocortin, Type 4/agonists , Humans , Inhibitory Concentration 50 , Molecular Structure , Pyridazines/chemical synthesis , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity RelationshipABSTRACT
The discovery of 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid analogs as potent human melanocortin-4 selective agonists is described.