sigma receptor ligands represent a new class of potential antipsychotic drugs. This paper presents the structure-activity relationships leading to novel disubstituted piperidine sigma ligands, which have little or no affinity for dopamine D2 receptors. Selectivity for sigma sites over dopamine D2 or serotonin 5-HT2 receptors appears to be governed by the chemical nature of the piperidine nitrogen substituent, its distance from the basic nitrogen, and its orientation relative to the other piperidine substituent. Several of these compounds have good oral potency in some animal models used to evaluate potential antipsychotic drugs. The N-cyclopropylmethyl ketones and ethers (e.g. 6i (DuP 734), 6q, 18a, and 18n) have the best in vivo potency. Compounds 6i (DuP 734) and 6q did not cause catalepsy in the rat, even at very high doses. On the basis of the pharmacology profiles of these sigma ligands, we propose these compounds may be effective antipsychotic drugs, which do not induce extrapyramidal side effects or tardive dyskinesia.

Screening of our chemical library using a rat corticotropin-releasing hormone (CRH) receptor assay led to the discovery that 2-anilinopyrimidine 15-1 weakly displaced [125I]-0-Tyr-oCRH from rat frontal cortex homogenates when compared to the known peptide antagonist alpha-helical CRH(9-41) (Ki = 5700 nM vs 1 nM). Furthermore, 15-1 weakly inhibited CRH-stimulated adenylate cyclase activity in the same tissue, but it was less potent than alpha-helical CRH(9-41) (IC50 = 20 000 nM vs 250 nM). Systematic structure-activity relationship studies, using the cloned human CRH1 receptor assay, defined the pharmacophore for optimal binding to hCRH1 receptors. Several high-affinity 2-anilinopyrimidines and -triazines were discovered, some of which had superior pharmacokinetic profiles in the rat. This paper describes the structure-activity studies which improved hCRH1 receptor binding affinity and pharmacokinetic parameters in the rat. Compound 28-17 (mean hCRH1 Ki = 32 nM) had a significantly improved pharmacokinetic profile in the rat (19% oral bioavailability at 30 mg/kg) as well as in the dog (20% oral bioavailability at 5 mg/kg) relative to the early lead structures.

Bioisosteric substitution was used as a tool to generate several new structural alternatives to the thiazolidine-2,4-dione and tetrazole heterocycles as potential antidiabetic agents. Among the initial leads that emerged from this strategy, a family of acidic azoles, isoxazol-3- and -5-ones and a pyrazol-3-one, showed significant plasma glucose-lowering activity (17-42% reduction) in genetically obese, diabetic db/db mice at a dose of 100 mg/kg/day x4. Structure-activity relationship studies determined that 5-alkyl-4-(arylmethyl)pyrazol-3-ones, which exist in solution as aromatic enol/iminol tautomers, were the most promising new class of potential antidiabetic agent (32-45% reduction at 20 mg/kg/d x4). Included in this work are convenient syntheses for several types of acidic azoles that may find use as new acidic bioisosteres in medicinal chemistry such as the antidiabetic lead 5-(trifluoromethyl)pyrazol-3-one (hydroxy tautomer) and aza homologs of the pyrazolones, 1,2,3-triazol-5-ones (hydroxy tautomer) and 1,2,3,4-tetrazol-5-one heterocycles. log P and pKa data for 15 potential acidic bioisosteres, all appended to a 2-naphthalenylmethyl residue so as to maintain a similar distance between the acidic hydrogen and arene nucleus, are presented. This new data set allows comparison of a wide variety of potential acid mimetics (pKa 3.78-10.66; log P -0.21 to 2.76) for future drug design.

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A new procedure for cyclohexenone annelation has been developed. Thus, alkylation of 4-isopropylcyclohexanone with allyl bromide gives, over several steps, ketone 8. Exposure to (trimethylsilyl)diazomethane and MeLi smoothly cyclized 8 to the cyclopentene 9 by insertion of the intermediate alkylidene carbene into the unactivated methylene CH. On debenzylation, ozonolysis, and subsequent aldol condensation, 9 is transformed into oxo-T-cadinol (1).

A general method for the cyclization of an unactivated 1,1-disubstituted alkene such as 1 to the corresponding cyclopentene 5 is described. Bromination followed by the addition of strong base in the same pot gave the vinyl bromide 3, which reacted further in situ to give the alkylidene carbene 4. This then inserted 1,5 into a C−H bond to give the cyclopentene 5.

In a preliminary communication (J. Med. Chem. 1989, 32, 11-13) a series of perfluoro-N-[4-(1H-tetrazol-5ylmethyl)phenyl]alkana mides (perfluoro anilides I), designed as novel analogues of ciglitazone, were reported to possess oral antidiabetic activity in two genetic animal models of non-insulin-dependent diabetes mellitus (NIDDM): obese (ob/ob) and diabetic (db/db) mice. In this report, the results from a structure-activity relationship (SAR) study of the series I are described. Comprehensive statistical analysis among the 86 analogues screened for blood glucose lowering in ob/ob mice was achieved by a new application of a general statistical procedure which made it possible to make meaningful comparisons between more than 140 separate experiments (N = 2966). Perfluoro anilides I lowered plasma glucose in the hyperglycemic ob/ob and db/db mice but not in euglycemic normal rats. In the hyperinsulinemic ob/ob mouse, decreases in plasma insulin levels paralleled the decline in plasma glucose. Potency and efficacy in the series was shown to be dependent on the length of the perfluorocarbon chain (RF) of I. Optimal activity occurred with the C7 and C8 RF chains. The more extensive SAR studies reported here, indicated that the lipophilic RF chain is the most important structural element of I since neither the phenyl nor tetrazole rings present in anilides I were necessary for antihyperglycemic activity while medium length (C7-C8) RF chains, especially the C7F15 chain, were shown to confer antihyperglycemic activity in ob/ob mice to a wide variety of structures.

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