title: Design, synthesis, and biological evaluation of novel potent and selective alphavbeta3/alphavbeta5 integrin dual inhibitors with improved bioavailability. Selection of the molecular core.
abstract: 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.
authors.affiliation: Johnson and Johnson Pharmaceutical Research & Development, L.L.C., 665 Stockton Drive, Suite 104, Exton, Pennsylvannia 19341, USA. JMARUGA1@prdus.jnj.com
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Marugán
authors.forename: Carl
authors.initials: C
authors.lastname: Manthey
authors.forename: Beth
authors.initials: B
authors.lastname: Anaclerio
authors.forename: Lou
authors.initials: L
authors.lastname: Lafrance
authors.forename: Tianbao
authors.initials: T
authors.lastname: Lu
authors.forename: Tom
authors.initials: T
authors.lastname: Markotan
authors.forename: Kristi A
authors.initials: KA
authors.lastname: Leonard
authors.forename: Carl
authors.initials: C
authors.lastname: Crysler
authors.forename: Stephen
authors.initials: S
authors.lastname: Eisennagel
authors.forename: Malini
authors.initials: M
authors.lastname: Dasgupta
authors.forename: Bruce
authors.initials: B
authors.lastname: Tomczuk
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D018938:Caco-2 Cells; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D016023:Integrins / Q000037:antagonists & inhibitors*; D051379:Mice; D010539:Permeability; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001583:Benzoxazoles; D007211:Indoles; D039302:Integrin alphaVbeta3; D016023:Integrins; D019030:Receptors, Vitronectin; D013876:Thiophenes; C064660:integrin alphaVbeta5