Preliminary pharmacokinetics and metabolism of novel non-steroidal antiandrogens in the rat: Relation of their systemic activity to the formation of a common metabolite

Biological properties of androgen receptor pure antagonist for treatment of castration‐resistant prostate cancer: Optimization from lead compound to CH5137291

“…The effect of CH5138514 and CH5166623 on plasma PSA levels and antitumor activity against LNCaP‐BC2 xenograft was almost the same as that of bicalutamide, and CH4933468 did not show any effect. Since CH compounds have a core structure which binds AR and has agonist activity, metabolism of CH compounds to the N ‐dealkyl or N ‐dearyl metabolites was analyzed 39. According to the results, CH4933468, CH5138514, and CH5166623 were metabolized to N ‐dealkyl or N ‐dearyl metabolite by mouse liver microsomes, the levels of metabolite were 3.8, 1.2, and 1.4 nmol/L, respectively, and the amount of agonist metabolite correlated with the reduction of efficacy in the LNCaP‐BC2 xenograft model.…”

Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

“…(Tables I and II) was developed in Europe for topical treatment of acne and alopecia (42,43), due to its short half life in vivo (less than one hour). Topical application not only avoids extensive hepatic metabolism (N-dealkylation) but also provides for effective regional treatment without systemic antiandrogen activity due to the formation of active metabolite (43,44). In comparison, structural analog RU58642 was shown to be orally active (35), and could significantly reduce prostate and seminal vesicle weights in intact male rats at dose rates from 1 to 30 mg/kg/day.…”

Fluridil, a Rationally Designed Topical Agent for Androgenetic Alopecia: First Clinical Experience

“…7 It is, nevertheless, probable that in humans, topical flutamide induces systemic antiandrogenic effects since at least 16% is transcutaneously resorbed. 8 Preclinical data of another oral antiandrogen, an N-substituted aryl hydantoin, RU-58841 (Figure l), suggested topical safety since the cutaneous resorption was low, 9,10 however, one of the metabolites proved stable and strongly antiandrogenic, 11 and further development was abandoned. Another agent used in AGA is minoxidil, an antihypertensive drug which, by a mechanism yet to be clarified, increases hair thickness and anagen count.…”