Marugán Juan José, Manthey Carl, Anaclerio Beth, Lafrance Lou, Lu Tianbao, Markotan Tom, Leonard Kristi A, Crysler Carl, Eisennagel Stephen, Dasgupta Malini, Tomczuk Bruce
Johnson and Johnson Pharmaceutical Research & Development, L.L.C., 665 Stockton Drive, Suite 104, Exton, Pennsylvannia 19341, USA.
J Med Chem. 2005 Feb 24;48(4):926-34. doi: 10.1021/jm049725u.
A novel series of potent and selective alpha(v)beta(3)/alpha(v)beta(5) dual( )()inhibitors was designed, synthesized, and evaluated against several integrins. These compounds were synthesized through a Mitsunobu reaction between the guanidinium mimetics and the corresponding central templates. Guanidinium mimetics with enhaced rigidity (i.e., (2-pyridylamino)propoxy versus the 2-(6-methylamino-2-pyridyl)ethoxy) led to improved activity toward alpha(v)beta(3). Exemplary oral bioavailability in mice was achieved using the indole central scaffold. Although, oral bioavailability was maintained when the indole molecular core was replace with the bioisosteric benzofuran or benzothiophene ring systems, it was found to not significantly impact the integrin activity or selectivity. However, the indole series displayed the best in vivo pharmacokinetic properties. Thus, the indole series was selected for further structure-activity relationships to obtain more potent alpha(v)beta(3)/alpha(v)beta(5) dual antagonist with improved oral bioavailability.
设计、合成了一系列新型强效且选择性的α(v)β(3)/α(v)β(5)双重抑制剂，并针对多种整合素进行了评估。这些化合物通过胍模拟物与相应的中心模板之间的 Mitsunobu 反应合成。具有增强刚性的胍模拟物（即(2-吡啶基氨基)丙氧基与 2-(6-甲基氨基-2-吡啶基)乙氧基）导致对α(v)β(3)的活性提高。使用吲哚中心支架在小鼠中实现了示例性的口服生物利用度。尽管当吲哚分子核心被生物电子等排体苯并呋喃或苯并噻吩环系统取代时口服生物利用度得以维持，但发现这对整合素活性或选择性没有显著影响。然而，吲哚系列显示出最佳的体内药代动力学性质。因此，选择吲哚系列进行进一步的构效关系研究，以获得具有改善口服生物利用度的更强效的α(v)β(3)/α(v)β(5)双重拮抗剂。
