To identify new CRF(1) receptor antagonists, an attempt to modify the bis-heterocycle moiety present in the top region of the dihydropyrrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF(1) receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.

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In an effort to discover novel CRF-1 receptor antagonists exhibiting improved physicochemical properties, a dihydropirrole[2,3]pyridine scaffold was designed and explored in terms of the SAR of the substitution at the pendent phenyl ring and the nature of the heterocyclic moieties present in the upper region of the molecule. Selective and potent compounds have been discovered endowed with reduced ClogP with respect to compounds known in the literature. Of particular relevance was the finding that the in vitro affinity of the series was maintained by reducing the overall lipophilicity. The results achieved by this exploration enabled the formulation of a novel hypothesis on the nature of the receptor binding pocket of this class of CRF-1 receptor antagonists, making use of in silico docking studies of the putative nonpeptidic antagonist binding site set up in house by homology modeling techniques.

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A series of 6-substituted purinyl alkoxycarbonyl amino acids were synthesized and evaluated for their ability to stimulate cytotoxic T lymphocytes (CTLs) and the mixed lymphocyte reaction (MLR). A few of these compounds, in particular [[5-[6-(N,N-dimethylamino)purin-9-yl]pentoxy]-carbonyl]D-arginine (BCH-1393, 4a), displayed an in vitro stimulation of CTLs comparable to interleukin 2 (IL 2). BCH-1393 increased the CTL response between 10(-9) M and 10(-5) M. Further, this potent in vitro activity was reflected as a significant increase in CTL cell number in vivo. However, immunophenotyping of some of the other equipotent compounds did not reveal a parallel relative increase in CTLs in vivo. It was difficult to formulate a rigorous structure-activity relationship based on in vitro CTL activity. Nevertheless, the activity was dependent upon the nature of the 6-substituent on the purine, the type and stereochemistry of the amino acid, and the distance and spatial freedom between the purine and amino acid as defined by the length and rigidity of the linker. These compounds were generally nontoxic, as exemplified by BCH-1393. BCH-1393 is a promising immunostimulant which may be targeted for those disease states which require an increased CTL or TH1 type response.

Depression and anxiety are psychiatric disorders that still constitute a major health concern worldwide. As a consequence of this high unmet need, more efficacious anxyolitic and antidepressant agents, exhibiting improved side-effect profiles, is highly desirable.[1] Corticotropin-releasing factor [2] (CRF) is a 41 amino acid peptide that interacts with two distinct CRF receptors, known as CRF 1 and CRF 2 . CRF is considered the primary regulator of the hypothalamus-pituitary-adrenal (HPA) axis and is implicated in the endocrine, behavioural, and autonomic response to stress via activation of the CRF 1 receptor. [3,4] As part of a broad chemical programme aimed towards the discovery of drug-like classes of CRF 1 receptor antagonists, which has proven to be highly challenging, we recently disclosed the synthesis and pharmacological characterization of[5] In particular, this initial effort led to the identification of compound 1 (Figure 1), a CRF 1 antagonist endowed with high in vitro affinity, a good pharmacokinetic (PK) profile in rats, and interesting activity in an in vivo animal model of anxiety. However, the progression of this compound was limited by its high clog P value, the strong inhibition of CYP1A2 isoform of cytochrome P450 (IC 50 < 0.1 mm), and a poor PK profile in dogs. Herein we report the identification of novel potent and selective CRF 1 antagonists. A distinctive feature of this new class of dihydropyrroloA C H T U N G T R E N N U N G [2,3-d]pyrimidine compounds is the presence of a pyrazole substituted with an additional heterocycle at the 'top' region. This characteristic sets it apart from most of the other known CRF 1 antagonists, which typically require a lipophilic alkylamino chain, and should result in improved physicochemical properties and metabolic stability. To expand our knowledge on the SAR around compound 1, we focused our attention on the substitution pattern of the pyrazole ring with diverse heterocycles. This also enabled modulation of the physicochemical parameters and, whenever possible, a decrease in the lipophilicity, thus giving compounds that exhibit better drug-like properties. To this end, we set out to elaborate a more rational approach by computational methods. Subsequently, we tied these findings with those of a broader exploration of the substitution pattern of the 'bottom' aryl/heteroaryl ring. Thus, the synthesis and SAR of templates 2 and 3 (Figure 1) are presented, as well as the in vitro and in vivo activity and the PK profile of the best compound identified.We initially focused our strategy on replacement of the CF 3 group present on the pyrazole fragment. Similarity searches based on both molecular electrostatic potential (MEP) and shape were performed. This approach [6] could lead to the iden-[a] F.

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