Dharmpal S. Dodd

Solid-phase synthesis of N,N′ substituted guanidines☆

Abstract An efficient method for the solid-phase synthesis of substituted guanidines is presented. A variety of alcohols react with resin-bound N,N′-bis(t-butoxycarbonyl)thiopseudourea under Mitsunobu conditions to give the corresponding alkylated thiopseudoureas. The guanidines are liberated from the resin upon exposure to ammonia or primary amines.

Small molecule antagonist of leukocyte function associated antigen-1 (LFA-1): structure-activity relationships leading to the identification of 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)nicotinic acid (BMS-688521).

Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclinical animal studies and clinical data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunological target. This article will detail the structure-activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clinical compound (1), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clinical trials.

Solid-phase synthesis of N,N′-substituted acylguanidines

An efficient method for the solid-phase synthesis of N,N′-substituted acylguanidines is presented. The key-step involves the N-acylation of resin immobilized S-methylisothiourea with a variety of carboxylic acids using PyAOP as the coupling agent. The resulting resin bound N-acyl-derivatives are reacted with a host of amines and the N-acyl,N′-alkyl(aryl)guanidines liberated from the resin upon exposure to TFA.

Solid phase synthesis of 1,5-diarylpyrazole-4-carboxamides: discovery of antagonists of the CB-1 receptor.

We have developed a solid phase synthesis route to 1,5-substituted pyrazole-4-carboxamides with three diversity points aimed at the discovery of new compounds as potential G-Protein coupled receptor (GPCR) ligands. The new chemistry involves acylation of a resin bound secondary amine with a β-ketoester via transamidation, conversion of the resulting β-ketoamide to the corresponding vinylogous amide, pyrazole formation upon reaction with a aryl hydrzine, and cleavage of the product from the resin. Using the reported methodology, we describe the syntheses of multiple arrays of pyrazoles that were used collectively to construct a library of more than 1000 analogues. Several members of this library displayed submicromolar antagonist activities at the cannabinoid subtype 1 (CB-1) receptor.