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Clinical studies have demonstrated that a prostaglandin E2 (PGE2) analogue had the property of increasing hair density and controlling hair loss in humans. However, prostaglandins are molecules which have a very short biological half-life period and which act in an autocrine or paracrine manner, reflecting a labile character due to a very active local metabolism of the prostaglandins. It therefore appears to be important, in order to maintain and/or increase hair density in humans, to preserve the endogenous reserves of PGE2 of the different compartment of the hair follicle or of its close cutaneous environment. NAD+-linked 15-hydroxyprostaglandin
dehydrogenase (15-PGDH) catalyzes the oxidation of 15(S)-hydroxyl group of prostaglandins and lipoxins resulting in the formation of 15-keto metabolites which exhibit greatly reduced biological activities. Therefore, this enzyme has been considered the key enzyme responsible for the inactivation of prostaglandins and lipoxins. Inhibitors of this enzyme may be of value on the hair density and/or growth. Previously, ciglitazone, an anti-diabetic thiazolidinedione, was found to be a potent inhibitor of 15-PGDH. Structure-activity analysis of available thiazolidinediones indicated that hydrophobicity of the moiety linking to phenyl ring through ether linkage as well as benzylidene configuration play important roles in inhibitory potency. Furthermore, N-methylation of 2,4-thiazolidinedione abolished the inhibitory activity. A series of benzylidene thiazolidinediones with varied ring structure and methylene bridge to phenyl ring through ether linkage were synthesized and assayed for inhibitory activity. It was found that compound CT-8 (5-[4-(cyclohexylethoxy)benzylidene]-2,4-thiazolidinedione) was the most potent inhibitor effective at nM range.