Synthesis, corticotropin-releasing factor receptor binding affinity, and pharmacokinetic properties of triazolo-, imidazo-, and pyrrolopyrimidines and -pyridines

The synthesis and CRF receptor binding affinities of several new series of N-aryltriazolo- and -imidazopyrimidines and -pyridines are described. These cyclized systems were prepared from appropriately substituted diaminopyrim idines or -pyridines by nitrous acid, orthoester, or acyl halide treatment. Variations of amino (ether) pendants and aromatic substituents have define d the structure-activity relationships of these series and resulted in the identification of a variety of high-affinity agents (K-i's < 10 nM). On the basis of this property and lipophilicity differences, six of these compoun ds (4d,i,n,x, 8k, 9a) were initially chosen for rat pharmacokinetic (PK) st udies. Good oral bioavailability, high plasma levels, and duration of four of these compounds (4d,i,n,x) prompted further PK studies in the dog follow ing both iv and oral routes of administration. Results from this work indic ated 4i,x had properties we believe necessary for a potential therapeutic a gent, and 4i(1) has been selected for further pharmacological studies that will be reported in due course.