Inhibition of steroid 5.alpha.-reductase by unsaturated 3-carboxy steroids

A series of unsaturated steroids bearing a 3-carboxy substituent has been prepared and assayed in vitro as inhibitors of human and rat prostatic steroid 5α-reductase (EC 1.3.1.30). It is proposed that the observed tight binding of the 3-androstene-3-carboxylic acids is due to mimicry of a putative, high-energy, enzyme-bound enolate intermediate formed during the NADPH-dependent conjugate reduction of testosterone by steroid 5α-reductase. These compounds were prepared through palladium(0)-catalyzed carbomethoxylations of enol(trifluoromethyl)sulfonates derived from 3-keto precursors. Modification of A and B ring unsaturation and substitution at C-3, −4, −6, and −11 was explored