1.Discovery of S-[5-amino-1-(4-fluorophenyl)-1H-pyrazol-4-yl]-[3-(2,3-dihydroxypropoxy)phenyl]methanone (RO3201195), an orally bioavailable and highly selective inhibitor of p38 MAP kinase.
Goldstein DM1, Alfredson T, Bertrand J, Browner MF, Clifford K, Dalrymple SA, Dunn J, Freire-Moar J, Harris S, Labadie SS, La Fargue J, Lapierre JM, Larrabee S, Li F, Papp E, McWeeney D, Ramesha C, Roberts R, Rotstein D, San Pablo B, Sjogren EB, So OY, Talamas FX, Tao W, Trejo A, Villasenor A, Welch M, Welch T, Weller P, Whiteley PE, Young K, Zipfel S. J Med Chem. 2006 Mar 9;49(5):1562-75.
A novel class of highly selective inhibitors of p38 MAP kinase was discovered from high throughput screening. The synthesis and optimization of a series of 5-amino-N-phenyl-1H-pyrazol-4-yl-3-phenylmethanones is described. An X-ray crystal structure of this series bound in the ATP binding pocket of unphosphorylated p38alpha established the presence of a unique hydrogen bond between the exocyclic amine of the inhibitor and threonine 106 which likely contributes to the selectivity for p38. The crystallographic information was used to optimize the potency and physicochemical properties of the series. The incorporation of the 2,3-dihydroxypropoxy moiety on the pyrazole scaffold resulted in a compound with excellent drug-like properties including high oral bioavailability. These efforts identified 63 (RO3201195) as an orally bioavailable and highly selective inhibitor of p38 which was selected for advancement into Phase I clinical trials.
2.Aminothienopyridazine inhibitors of tau aggregation: evaluation of structure-activity relationship leads to selection of candidates with desirable in vivo properties.
Ballatore C1, Crowe A, Piscitelli F, James M, Lou K, Rossidivito G, Yao Y, Trojanowski JQ, Lee VM, Brunden KR, Smith AB 3rd. Bioorg Med Chem. 2012 Jul 15;20(14):4451-61. doi: 10.1016/j.bmc.2012.05.027. Epub 2012 May 23.
Previous studies demonstrated that members of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors exhibit a promising combination of in vitro activity as well as favorable pharmacokinetic properties (i.e., brain-penetration and oral bioavailability). Here we report the synthesis and evaluation of several new analogues. These studies indicate that the thienopyridazine core is essential for inhibition of tau fibrillization in vitro, while the choice of the appropriate scaffold decoration is critical to impart desirable ADME-PK properties. Among the active, brain-penetrant ATPZ inhibitors evaluated, 5-amino-N-cyclopropyl-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide (43) was selected to undergo maximum tolerated dose and one-month tolerability testing in mice. The latter studies revealed that this compound is well-tolerated with no notable side-effects at an oral dose of 50mg/kg/day.