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Further optimization of the biaryl amide series via extensively exploring structure–activity relationships resulted in potent and subtype selective M1 agonists exemplified by compounds 9a and 9j with good rat PK properties including CNS penetration. Synthesis, structure–activity relationships, subtype selectivity for M1 over M2–5, and DMPK properties of these novel compounds are described.

A series of N-arylpiperazine camphor sulfonamides was discovered as novel CXCR3 antagonists. The synthesis, structure–activity relationships, and optimization of the initial hit that resulted in the identification of potent and selective CXCR3 antagonists are described.

SAR exploration of the central diamine, benzyl, and terminal aminoalkoxy regions of the N-cyclic azaalkyl benzamide series led to the identification of very potent human urotensin-II receptor antagonists such as 1a with a Ki of 4 nM. The synthesis and structure–activity relationships (SAR) of N-cyclic azaalkyl benzamides are described.

A series of 2-aminomethyl piperidines has been discovered as novel urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that resulted in the identification of potent, cross-species active, and functional urotensin-II receptor antagonists such as 1a and 11a are described.

High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described.

An efficient, asymmetric solid-phase synthesis of benzothiadiazine-substituted tetramic acids is reported. Starting from commercially available chiral Fmoc-protected alpha-amino acids loaded onto Wang resin, Fmoc removal, reductive amination followed by amide bond formation, and base-catalyzed cyclization with simultaneous cleavage from the resin provided the desired products. Compounds described are potent inhibitors of the hepatitis C virus RNA-dependent RNA polymerase.

High throughput screening of the corporate compound collection led to the discovery of a novel series of substituted aminoalkoxybenzyl pyrrolidines as human urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that led to the identification of a truncated sub-series, represented by SB-436811 (1a), are described.

A protocol for monoacylation of unprotected symmetrical diamines with a resin-bound benzoic acid is described. The nature of the resin (gel-based polystyrene vs highly crosslinked macroporous polystyrene) was found to play a minor role in acylation selectivity. Rather, the concentration of the diamine dictates the ratio of mono- and diacylated products. Thus, by employing a high concentration of symmetrical diamine (e.g., 1 M, 20 equiv), monoacylation can be selectively achieved for a variety of unprotected symmetrical alkyl and aryl diamines.

The use of a multiplex mimetic assay led us to identify 1,4-dihydropyrimidines with potent and selective calcitonin receptor mimetic activity. Subsequent modification of the dihydropyrimidine scaffold led to a series of molecules that were efficacious in a neonatal mouse calvaria in vitro model. Dihydropyrimidine 5h, in particular, was identified as a calcitonin mimetic (EC50=6 μM), active in-vivo in the Weanling rat model when administered subcutaneously.

A robust ‘catch and release’ synthesis of fused 2-alkylthio-3-substituted-pyrimidinones mediated by the polymer-bound base P-BEMP is described. This reengineered synthesis combines the efficiency of the classical synthesis (three steps, three diversity points) with the practical benefits of resin-bound reagents. The solution-phase strategy, reagent compatibility, and the results of a representative 48-member combinatorial library are described and presented herein.

The melanocortin-4 receptor (MC4) modulates physiological functions such as feeding behavior, nerve regeneration, and drug addiction. Using a high throughput screen based on 125 I-NDP-MSH binding to the human MC4 receptor, we discovered 2,3-diaryl-5-anilino[1,2,4]thiadiazoles 3 as potent and selective MC4 receptor agonists. Through SAR development on the three attached aryl rings, we improved the binding affinity from 174 nM to 4.4 nM IC 50 . When delivered intraperitoneally, compounds 3a , 3b , and 3c induced significant inhibition of food intake in a fasting-induced feeding model in rats. When delivered orally, these compounds lost activity, mainly due to rapid metabolism to inactive imidoylthiourea reduction products.

The Sonogashira reaction of a resin-bound iodobenzoic acid with trimethylsilyl acetylene followed by TBAF desilylation provided a polymer-supported aryl acetylene, 3. Treatment of 3 with an aldehyde and a secondary amine in dioxane in the presence of CuCl catalyst results in the generation of resin-bound propargylamines. The final products (4) were cleaved from the resin and obtained in excellent yields and purity.

The preparation of 1-alkyl-2-alkylthio-5-carbamoylbenzimidazoles 7 is described. The cyclization of a resin bound o -phenylenediamine 4 with thiocarbonyldiimidazole (TCD) in THF provided a benzimidazole-2-thione 5 . Treatment of 5 with benzylic halides in the presence of DIEA resulted in the resin bound 1-alkyl-2-alkylthio-5-carbamoylbenzimidazoles 6 . The final products were cleaved from the resin and obtained in from 74% to 99% yields.

A procedure for preparing substituted aminosulfonyl ureas on solid support is described. Chemoselective reaction of chlorosulfonyl isocyanate with the Wang resin followed by reaction with an amine provides resin-bound substituted aminosulfonylcarbamates. Heating of the resultant resin in THF with a second amine provides the desired substituted aminosulfonyl ureas in good yield and purity. © 1997 Elsevier Science Ltd.

The structural optimization for binding affinity and attempted modification of agonist function of a nonpeptide ligand of the human C5a receptor is described.

Screening of our sample collection for novel structures with endothelin receptor (ET A and ET B ) binding affinity, resulted in the discovery of structure I (R = H). This unique bicyclic diacid elicited modest affinity for both cloned human receptors (0.8 μM, ET A and 7.9 μM, ET B ). Substitution at ‘R’ resulted in increased affinity for both receptors.

Non-peptide ligands for peptide receptors for the G-protein-coupled type are generally antagonists, except in the opiate system. Recently, it was observed that a subset of biphenylimidazole derivatives surprisingly possessed angiotensin-like activity in vivo. In COS-7 cells transfected with the rat AT1 receptor a prototype of these compounds, L-162,313 stimulated phosphoinositide hydrolysis with an EC50 of 33 +/- 11 nM. The maximal response to the compound was 50% of that of angiotensin II in COS-7 cells but only 3% in stably transfected Chinese hamster ovary cells. The agonistic effect of L-162,313 was blocked by the AT1-specific antagonist L-158,809 and was not observed in untransfected cells. In Chinese hamster ovary cells, L-162,313 also acted as an insurmountable antagonist of the angiotensin stimulated phosphoinositide hydrolysis. In contrast to previously tested non-peptide ligands, L-162,313 bound with reasonably high affinity to the Xenopus laevis AT1 receptor. In the human receptor, the binding of L-162,313 was found to be unaffected by point mutations in transmembrane segments III and VII, which impaired the binding of biphenylimidazole antagonists. Substitutions in the extracellular domains of the human and rat receptor, which impaired the binding of angiotensin II, did not affect the binding of L-162,313. It is concluded that a subset of biphenylimidazole compounds can act as high affinity partial agonists on the AT1 receptor. These compounds have molecular interactions with the receptor which appear to differ both from that of the structurally similar non-peptide antagonists and from that of their functional counterpart, the peptide agonist.

A series of subnanomolar (IC50 triazolinone-based AT1/AT2-balanced AII antagonists has been identified. The 70-240-fold gain in AT2 activity relative to prototype compounds was achieved by the introduction of a 5-acylamino group on the N2-aryl moiety and the addition of (3-F-5'-Pr)biphenyl substituents on 4. These analogues exhibited AT2/AT1 IC50 rations of ≤1 in multiple assay systems including human adrenal.

Inspired by the modest success of a phenoxyphenylacetic acid ( I ) biphenyl tetrazole replacement, 1,3-benzodioxole-2-carboxylates and 1,3-benzodithiole-2-carboxylates ( II ) and their respective tetrazole analogs ( III ) were investigated as AII antagonists. These compounds, essentially conformationally restricted analogs of the phenoxyphenylacetic acid series, proved to be quite potent in vitro .

The biphenyl fragment of the potent angiotensin II receptor antagonist L-158,809 was replaced by a phenylthiophene and a phenylfuran moiety. Replacement of the tetrazole-bearing phenyl by a thiophene resulted in a small loss in binding affinity (

Selective radioligands of the angiotensin II AT1 receptor subtype have been prepared. Radiolabeled Losartan (DuP 753)1,2, L-158,641 (EXP3174)3 and L-158,8094,5 were prepared from a common bromobiphenyl intermediate. The key step in the synthesis is the selective aromatic monobromination of 2-cyano-4′-methylbiphenyl. Selective radioligands of the angiotensin II AT1 receptor subtype have been prepared from a common bromobiphenyl intermediate. The key step in the synthesis is the selective aromatic monobromination of 2-cyano-4′-methylbiphenyl

As part of an effort to develop human renin inhibitors with improved biovailability, macrocyclic renin inhibitors 1 and 2 were prepared. These macrocycles were constructed from an analog of “ACHPA” ((3S, 4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid) 1 which incorporates a 2(S)-4-butenyl chain. A key step in the assembly of these macrocycles was the stereoselective synthesis of the 2(S)-substituted ACHPA derivative 3 , utilizing the Evans chiral oxazolidone aldol protocol. 2

As part of an effort to design human renin inhibitors with improved bioavailability, the amino-terminal Phe-His element present in many classes of renin inhibitors was replaced by a sulfone containing isostere.

The anomeric hydroxyl group of various pyranose hemiacetals can be esterified with inversion of configuration, conveniently, mildly and on large-scale using triphenylphosphine (TPP), with either diisopropylazodicarboxylate (DIAD) or diethylazodicarboxylate (DEAD) and a carboxylic acid in THF at either −50° C or at room temperature.

The antineoplastic glycoside (+)-phyllanthostatin 3 ( 4 ) has been synthesized for the first time, together with its aglycone (+)-phyllanthocindiol ( 5 ).