Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K(i) against DPP4, DPP8, and DPP9 of 0.37 nM, 2.2, and 5.7 muM, respectively, showed a significant improvement in insulin response after single doses of 3 and 10 mumol/kg in ob/ob mice.
Wang W, Devasthale P, Wang A, Harrity T, Egan D, Morgan N, Cap M, Fura A, Klei HE, Kish K, Weigelt C, Sun L, Levesque P, Li YX, Zahler R, Kirby MS, Hamann LG (2011) 7-Oxopyrrolopyridine-derived DPP4 inhibitors-mitigation of CYP and hERG liabilities via introduction of polar functionalities in the active site Bioorganic & Medicinal Chemistry Lett21: 6646-51
Wang W, Devasthale P, Wang A, Harrity T, Egan D, Morgan N, Cap M, Fura A, Klei HE, Kish K, Weigelt C, Sun L, Levesque P, Li YX, Zahler R, Kirby MS, Hamann LG (2011) Bioorganic & Medicinal Chemistry Lett21: 6646-51