ABSTRACT
A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFß receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFß induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.
Subject(s)
Cicatrix/prevention & control , Drug Discovery , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Skin/drug effects , Animals , Models, Molecular , Phosphorylation , Rats , Receptor, Transforming Growth Factor-beta Type IABSTRACT
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
We describe a series of 1,2,4-oxadiazoles, which are potent antagonists of the integrin alpha(v)beta3 and, in addition, show selectivity relative to the other beta3 integrin alpha(IIb)beta3. In whole cells, the majority of these analogs also demonstrated modest selectivity against other alpha(v) integrins such as alpha(v)beta1 and alpha(v)beta6.