title: Binding thermodynamics of substituted diaminopyrimidine renin inhibitors.
abstract: Renin is an aspartyl protease involved in the production of angiotensin II, a potent vasoconstrictor. Renin inhibitors can prevent blood vessel constriction and therefore could be useful for the treatment of hypertension. High-throughput screening efforts identified a small molecule renin inhibitor with a core substituted diaminopyrimidine ring. Parallel medicinal chemistry efforts based on this lead resulted in compound 1. A complex of 1 bound to renin was crystallized, and structural data were obtained by X-ray diffraction. The structure indicated that there were adjacent unoccupied binding pockets. Synthetic efforts were initiated to extend functionality into these pockets so as to improve affinity and adjust pharmacokinetic parameters. Thermodynamics data for inhibitor binding to renin were also collected using isothermal titration calorimetry. These data were used to help guide inhibitor optimization by suggesting molecular alterations to improve binding affinity from both thermodynamic and structural perspectives. The addition of a methoxypropyl group extending into the S3 subpocket improved inhibitor affinity and resulted in greater binding enthalpy. Initial additions to the pyrimidine ring template that extended into the large hydrophobic S2 pocket did not improve affinity and dramatically altered the thermodynamic driving force for the binding interaction. Binding of the core template was enthalpically driven, whereas binding of initial inhibitors with S2 extensions was both enthalpically and entropically driven but lost significant binding enthalpy. Additional electrostatic interactions were then incorporated into the S2 extension to improve binding enthalpy while taking advantage of the favorable entropy.
authors.affiliation: Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. ronald.w.sarver@pfizer.com
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Sarver
authors.forename: Jeanette
authors.initials: J
authors.lastname: Peevers
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Cody
authors.forename: Fred L
authors.initials: FL
authors.lastname: Ciske
authors.forename: Jim
authors.initials: J
authors.lastname: Dyer
authors.forename: S Donald
authors.initials: SD
authors.lastname: Emerson
authors.forename: Jeanne C
authors.initials: JC
authors.lastname: Hagadorn
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Holsworth
authors.forename: Mehran
authors.initials: M
authors.lastname: Jalaie
authors.forename: Michael
authors.initials: M
authors.lastname: Kaufman
authors.forename: Michelle
authors.initials: M
authors.lastname: Mastronardi
authors.forename: Patrick
authors.initials: P
authors.lastname: McConnell
authors.forename: Noel A
authors.initials: NA
authors.lastname: Powell
authors.forename: John
authors.initials: J
authors.lastname: Quin
authors.forename: Chad A
authors.initials: CA
authors.lastname: Van Huis
authors.forename: Erli
authors.initials: E
authors.lastname: Zhang
authors.forename: Igor
authors.initials: I
authors.lastname: Mochalkin
mesh_terms: D002151:Calorimetry; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics; D014961:X-Ray Diffraction; D000092502:Renin Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D011725:Pyridines; D000092502:Renin Inhibitors