Dihydrotestosterone (DHT), a metabolite of the predominant circulating androgen testosterone, is recognized as a principal mediator of benign prostatic hyperplasia (BPH) and implicated in prostatic cancer and skin disorders including acne, androgenic alopecia, and hirsutism. Thus, potent inhibitors of steroid 5α-reductase (SR), the NADPH-dependent enzyme responsible for DHT production, are sought. Steroidal inhibitors like the C-3 carboxylic acids (epristeride, 1; 2) and 4-aza class (finasteride, 3) selectively inhibit the prostate-predominant type-2 SR isozyme. Prompted by the promising activities of D-ring-deleted analogs (4, 5), we screened nonsteroidal aryl carboxylic acids retaining key A-ring features of the enolate transition state mimetic design strategy. This uncovered two classes of very potent type-2 selective SR inhibitors: p-toluoylbenzophenonecarboxylic acid (6) with an apparent inhibition constant (Ki,app) of 10 nM against recombinant human type-2 SR and 5-(benzyloxy)indole-2-carboxylic acid (28) with a Ki of 40 nM. Neither compound significantly inhibited recombinant human type-1 SR at concentrations approaching their solubility limits. We describe preliminary structure-activity relationships (SAR) for these classes: in the benzoylbenzophenone series, C-ring substitution/saturation and B-C linker replacements (ether, methylene, oxoethylene) are tolerated (ether linkers increase potency 5-8-fold), while A-B linker substitution with methylene/hydroxymethylene reduces activity; the A-ring carboxylic acid and C-ring are critical for potency. In the indole series, N-methylation affects potency differently (8-fold decrease for 28→29, 2-3-fold increase for 30→31), and 5/6-position B-ring substitution is preferred. Compound 6 exhibits uncompetitive inhibition kinetics versus testosterone, suggesting a binding mode analogous to steroidal carboxylic acids via charge complementarity with the oxidized cofactor NADP+. Substituted benzophenone- and indolecarboxylic acids are potent and selective inhibitors of human type-2 SR, with ongoing work to further characterize SAR and inhibition mechanisms.