ABSTRACT
A series of aminomethylpyrazoles were prepared and evaluated using cell-based Smoothened beta-lactamase reporter assay and Smoothened binding assay. Potent Smoothened antagonists 10k and 10l were found to inhibit hair growth in vivo in the C3H/HeN mouse hair growth model. The more selective compound 10l was tested negative in the 3T3 NRU assay, indicating a low risk for causing photo-irritation and was efficacious using the C3H/HeN mouse hair growth model although it was slightly less efficacious than that of the reference compound eflornithine (7).
Subject(s)
Azetidines/chemistry , Hair/drug effects , Pyrazoles/chemistry , Animals , Azetidines/chemical synthesis , Azetidines/pharmacology , Eflornithine/pharmacology , Hair/growth & development , Mice , Mice, Knockout , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Structure-Activity RelationshipABSTRACT
4-((1 R,2 R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile [PF-0998425, (-)- 6a] is a novel, nonsteroidal androgen receptor antagonist for sebum control and treatment of androgenetic alopecia. It is potent, selective, and active in vivo. The compound is rapidly metabolized systemically, thereby reducing the risk of unwanted systemic side effects due to its primary pharmacology. (-)- 6a was tested negative in the 3T3 NRU assay, validating our rationale that reduction of conjugation might reduce potential phototoxicity.
Subject(s)
Androgen Receptor Antagonists , Cyclohexanols/chemical synthesis , Cyclohexanols/pharmacology , Nitriles/chemical synthesis , Nitriles/pharmacology , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/pharmacology , Skin , Crystallography, X-Ray , Cyclohexanols/chemistry , Drug Design , Ligands , Models, Molecular , Molecular Structure , Nitriles/chemistry , Photosensitizing Agents/chemistry , Receptors, Androgen/chemistry , Receptors, Androgen/metabolism , Skin/drug effects , Skin/metabolism , Steroids/chemistry , Structure-Activity RelationshipABSTRACT
Quinazolinones 8 and pyrido[3,4-d]pyrimidin-4-ones 9 as orally active and specific matrix metalloproteinase-13 inhibitors were discovered for the treatment of osteoarthritis. Starting from a high-through-put screening (HTS) hit thizolopyrimidin-dione 7, we obtained two chemotypes, 8 and 9, using computer-aided drug design (CADD) and methodical structure-activity relationship (SAR) studies. They occupy the unique S 1'-specificity pocket and do not bind to the Zn(2+) ion. Some pyrido[3,4-d]pyrimidin-4-ones, such as 10a, possess favorable absorption, distribution, metabolism, and elimination (ADME) and safety profiles. 10a effectively prevents cartilage damage in rabbit animal models of osteoarthritis without inducing musculoskeletal side effects when given at extremely high doses to rats.
Subject(s)
Matrix Metalloproteinase Inhibitors , Osteoarthritis/drug therapy , Pyridines/chemical synthesis , Pyrimidines/chemical synthesis , Quinazolinones/chemical synthesis , Administration, Oral , Animals , Biological Availability , Male , Pyridines/pharmacokinetics , Pyridines/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Quinazolinones/pharmacokinetics , Quinazolinones/pharmacology , Rabbits , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A series of amino-pyridines were synthesized and evaluated for androgen antagonist activities. Among these compounds, (R)-(+)-6-[methyl-(1-phenyl-ethyl)-amino]-4-trifluoromethyl-nicotinonitrile was the most active example of this class. This compound displayed potent androgen receptor antagonist activity as well as favorable pharmacokinetic characteristics for a potential topical agent. It also demonstrated remarkable potency for stimulating hair growth in a male C3H mouse model as well as reducing sebum production in the male Syrian hamster ear model.
Subject(s)
Aminopyridines/chemistry , Aminopyridines/pharmacology , Androgen Receptor Antagonists , Hair/drug effects , Hair/growth & development , Sebum/drug effects , Sebum/metabolism , Aminopyridines/chemical synthesis , Animals , Dose-Response Relationship, Drug , Male , Mice , Mice, Inbred C3H , Models, Molecular , Molecular Structure , Receptors, Androgen/metabolism , Structure-Activity RelationshipABSTRACT
A series of substituted 4-aryl-2-trifluoromethylbenzonitrile analogs were evaluated in the human androgen receptor binding and cellular functional assays. Analogs with sufficient in vitro binding and cellular potency (IC(50)<200 nM) were tested in the progesterone receptor binding assay for selectivity and in the Golden Syrian hamster ear model for in vivo efficacy. Within the series, compound 4 e was identified to be the most active analog in vivo (wax ester inhibition=86%).
Subject(s)
Androgen Receptor Antagonists , Fluorine/chemistry , Nitriles/chemistry , Nitriles/pharmacology , Receptors, Androgen/metabolism , Sebum/drug effects , Sebum/metabolism , Humans , Inhibitory Concentration 50 , Methylation , Molecular Structure , Nitriles/chemical synthesis , Structure-Activity RelationshipABSTRACT
Synthesis, pharmacology, and pharmacokinetic profiles of (1R, 2S)-4-(2-cyano-cyclohexyl-oxy)-2-trifluoromethyl-benzonitrile are reported. This compound demonstrated remarkable potency for stimulating hair growth in a male C3H mouse model as well as reducing sebum production in the male Syrian hamster ear model.
Subject(s)
Androgen Antagonists/pharmacology , Hair/growth & development , Hydrocarbons, Fluorinated/pharmacology , Nitriles/pharmacology , Sebum , Animals , Cricetinae , Hydrocarbons, Fluorinated/pharmacokinetics , Male , Mesocricetus , Mice , Models, Molecular , Nitriles/pharmacokineticsABSTRACT
Interleukin-8 modulation is implicated in many inflammatory and cancer diseases. Starting from a mass-screening hit, the synthesis and structure-activity relationship of 2-amino-3-heteroarylquinoxalines as non-peptide, small molecule interleukine-8 receptor antagonists have been developed. The optimized derivatives, PD 0210293 (13y) and PD 0220245 (13r), show inhibition of both IL-8 receptor binding and IL-8-mediated neutrophil chemotaxis.
Subject(s)
Quinoxalines , Receptors, Interleukin-8A/antagonists & inhibitors , Anti-Inflammatory Agents/chemistry , Antineoplastic Agents/chemistry , Calcium/metabolism , Chemotaxis/drug effects , Diamines/chemical synthesis , Diamines/chemistry , Diamines/pharmacology , Humans , Quinoxalines/chemical synthesis , Quinoxalines/chemistry , Quinoxalines/pharmacology , Receptors, Interleukin-8A/metabolism , Structure-Activity RelationshipABSTRACT
[reaction: see text] By taking advantage of the alpha- and gamma-activation of chloropyridines as well as palladium-mediated reactions, all four possible benzo[4,5]furopyridine tricyclic heterocycles, benzo[4,5]furo[2,3-b]pyridine, benzo[4,5]furo[2,3-c]pyridine, benzo[4,5]furo[3,2-c]pyridine, and benzo[4,5]furo[3,2-b]pyridine, are efficiently synthesized from 2-chloro-3-iodopyridine, 3-chloro-4-stannylpyridine, 4-chloro-3-iodopyridine, and 2-chloro-3-hydroxypyridine, respectively.
